Pyrazolo[3,4-b] pyridine compounds, and their use as phosphodiesterase inhibitors

ABSTRACT

The invention relates to a compound of formula (I) or a salt thereof:  
                 
wherein: 
     R 1  is C 1-4 alkyl, C 1-3 fluoroalkyl, —CH 2 CH 2 OH or —CH 2 CH 2 CO 2 C 1-2 alkyl;    R 2  is a hydrogen atom (H), methyl or C 1 fluoroalkyl;    R 3  is optionally substituted C 3-8 cycloalkyl or optionally substituted mono-unsaturated-C 5-7 cycloalkenyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc);  
                 
   in which n 1  and n 2  independently are 1 or 2; and in which Y is O, S, SO 2 , or NR 10 ;    or R 3  is a bicyclic group (dd) or (ee):  
                 
   and wherein X is NR 4 R 5  or OR 5a . The compounds are phosphodiesterase (PDE) inhibitors, in particular PDE4 inhibitors. Also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal such as a human, for example chronic obstructive pulmonary disease (COPD), asthma, or allergic rhinitis.

The present invention relates to pyrazolopyridine compounds, processesfor their preparation, intermediates usable in these processes, andpharmaceutical compositions containing the compounds. The invention alsorelates to the use of the pyrazolopyridine compounds in therapy, forexample as inhibitors of phosphodiesterases and/or for the treatmentand/or prophylaxis of inflammatory and/or allergic diseases such aschronic obstructive pulmonary disease (COPD), asthma, rheumatoidarthritis or allergic rhinitis.

U.S. Pat. No. 3,979,399, U.S. Pat. No. 3,840,546, and U.S. Pat. No.3,966,746 (E.R.Squibb & Sons) disclose 4-amino derivatives ofpyrazolo[3,4-b]pyridine-5-carboxamides wherein the 4-amino group NR₃R₄can be an acyclic amino group wherein R₃ and R₄ may each be hydrogen,lower alkyl (e.g. butyl), phenyl, etc.; NR₃R₄ can alternatively be a3-6-membered heterocyclic group such as pyrrolidino, piperidino andpiperazino. The compounds are disclosed as central nervous systemdepressants useful as ataractic, analgesic and hypotensive agents.

U.S. Pat. No. 3,925,388, U.S. Pat. No. 3,856,799, U.S. Pat. No.3,833,594 and U.S. Pat. No. 3,755,340 (E.R.Squibb & Sons) disclose4-amino derivatives of pyrazolo[3,4-b]pyridine-5-carboxylic acids andesters. The 4-amino group NR₃R₄ can be an acyclic amino group wherein R₃and R₄ may each be hydrogen, lower alkyl (e.g. butyl), phenyl, etc.;NR₃R₄ can alternatively be a 5-6-membered heterocyclic group in which anadditional nitrogen is present such as pyrrolidino, piperidino,pyrazolyl, pyrimidinyl, pyridazinyl or piperazinyl. The compounds arementioned as being central nervous system depressants useful asataractic agents or tranquilisers, as having antiinflammatory andanalgesic properties. The compounds are mentioned as increasing theintracellular concentration of adenosine-3′,5′-cyclic monophosphate andfor alleviating the symptoms of asthma.

H. Hoehn et al., J. Heterocycl. Chem., 1972, 9(2), 235-253 discloses aseries of 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid derivatives with4-hydroxy, 4-chloro, 4-alkoxy, 4-hydrazino, and 4-amino substituents.

CA 1003419, CH 553 799 and T. Denzel, Archiv der Pharmazie, 1974,301(3), 177-186 disclose 4,5-disubstituted 1H-pyrazolo[3,4-b]pyridinesunsubstituted at the 1-position.

Japanese laid-open patent application JP-2002-20386-A (Ono Yakuhin KogyoKK) published on 23 Jan. 2002 discloses pyrazolopyridine compounds ofthe following formula:

-   wherein R¹ denotes 1) a group —OR⁶, 2) a group —SR⁷, 3) a C2-8    alkynyl group, 4) a nitro group, 5) a cyano group, 6) a C1-8 alkyl    group substituted by a hydroxy group or a C1-8 alkoxy group, 7) a    phenyl group, 8) a group —C(O)R⁸, 9) a group —SO₂NR⁹R¹⁰, 10) a group    —NR¹¹SO₂R¹², 11) a group —NR¹³C(O)R¹⁴ or 12) a group —CH═NR¹⁵. R⁶    and R⁷ denote i) a hydrogen atom, ii) a C1-8 alkyl group, iii) a    C1-8 alkyl group substituted by a C1-8 alkoxy group, iv) a    trihalomethyl group, v) a C3-7 cycloalkyl group, vi) a C1-8 alkyl    group substituted by a phenyl group or vii) a 3-15 membered mono-,    di- or tricyclic hetero ring containing 14 nitrogen atoms, 1-3    oxygen atoms and/or 1-3 sulphur atoms. R² denotes 1) a hydrogen atom    or 2) a C1-8 alkoxy group. R³ denotes 1) a hydrogen atom or 2) a    C1-8 alkyl group. R⁴ denotes 1) a hydrogen atom, 2) a C1-8 alkyl    group, 3) a C3-7 cycloalkyl group, 4) a C1-8 alkyl group substituted    by a C3-7 cycloalkyl group, 5) a phenyl group which may be    substituted by 1-3 halogen atoms or 6) a 3-15 membered mono-, di- or    tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen    atoms and/or 1-3 sulphur atoms. R⁵ denotes 1) a hydrogen atom, 2) a    C1-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a C1-8 alkyl group    substituted by a C3-7 cycloalkyl group or 5) a phenyl group which    may be substituted by 1-3 substituents. In group R³, a hydrogen atom    is preferred. In group R⁴, methyl, ethyl, cyclopropyl, cyclobutyl or    cyclopentyl are preferred. The compounds of JP-2002-20386-A are    stated as having PDE4 inhibitory activity and as being useful in the    prevention and/or treatment of inflammatory diseases and many other    diseases.

EP 0 076 035 A1 (ICI Americas) discloses pyrazolo[3,4-b]pyridinederivatives as central nervous system depressants useful astranquilisers or ataractic agents for the relief of anxiety and tensionstates.

The compound cartazolate, ethyl4-(n-butylamino)-1-ethyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylate, isknown. J. W. Daly et al., Med. Chem. Res., 1994, 4, 293-306 and D. Shiet al., Drug Development Research, 1997, 42, 41-56 disclose a series of4-(amino)substituted 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acidderivatives, including ethyl4-cyclopentylamino-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,and their affinities and antagonist activities at A₁- andA_(2A)-adenosine receptors, and the latter paper discloses theiraffinities at various binding sites of the GABAA-receptor channel. S.Schenone et al., Bioorg. Med. Chem. Lett., 2001, 11, 2529-2531 and F.Bondavalli et al., J. Med. Chem., 2002, vol. 45 (Issue 22, 24 Oct. 2002,allegedly published on Web Sep. 24, 2002), pp. 4875-4887 disclose aseries of4-amino-1-(2-chloro-2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid ethyl esters as A₁-adenosine receptor ligands.

WO 02/060900 A2 appears to disclose, as MCP-1 antagonists for treatmentof allergic, inflammatory or autoimmune disorders or diseases, a seriesof bicyclic heterocyclic compounds with a —C(O)—NR⁴—C(O)—NR⁵R⁶substituent, including isoxazolo[5,4-b]pyridines and1H-pyrazolo[3,4-b]pyridines (named as pyrazolo[5,4-b]pyridines) with the—C(O)—NR⁴—C(O)—NR⁵R⁶ group as the 5-substituent and optionallysubstituted at the 1-, 3-, 4-, and/or 6-positions. Bicyclic heterocycliccompounds with a —C(O)NH₂ substituent instead of the—C(O)—NR⁴—C(O)—NR⁵R⁶ substituent are alleged to be disclosed in WO02/060900 as intermediates in the synthesis of the —C(O)—NR⁴—C(O)—NR⁵R⁶substituted compounds.

It is desirable to find new compounds which bind to, and preferablyinhibit, phosphodiesterase type IV (PDE4).

The present invention provides a compound of formula (I) or a saltthereof (in particular, a pharmaceutically acceptable salt thereof):

wherein:

-   R¹ is C₁₋₄alkyl, C₁₋₃fluoroalkyl, —CH₂CH₂OH or —CH₂CH₂CO₂C₁₋₂alkyl;-   R² is a hydrogen atom (E), methyl or C₁fluoroalkyl;-   R³ is optionally substituted C₃₋₈cycloalkyl or optionally    substituted mono-unsaturated-C₅₋₇cycloalkenyl or an optionally    substituted heterocyclic group of sub-formula (aa), (bb) or (cc);-   in which n¹ and n² independently are 1 or 2; and in which Y is O, S,    SO₂, or NR¹⁰; where R¹⁰ is a hydrogen atom (H), C₁₋₄alkyl (e.g.    methyl or ethyl), C₁₋₂fluoroalkyl, CH₂C(O)NH₂, C(O)NH₂,    C(O)—C₁₋₂alkyl, C(O)—C₁fluoroalkyl or —C(O)—CH₂O—C₁₋₂alkyl;-   and wherein in R³ the C₃₋₈cycloalkyl or the heterocyclic group of    sub-formula (aa), (bb) or (cc) is optionally substituted with one or    two substituents independently being (e.g. being) oxo (═O); OH;    C₁₋₂alkoxy; C₁₋₂fluoroalkoxy (e.g. trifluoromethoxy); NHR²¹ wherein    R²¹ is a hydrogen atom (H or C₁₋₅ straight-chain alkyl (e.g. H or    C₁₋₄ straight-chain alkyl); C₁₋₂alkyl; C₁₋₂fluoroalkyl (e.g.    C₁fluoroalkyl such as —CH₂F or —CHF₂); —CH₂OH; —CH₂CH₂OH; —CH₂NHR²²    wherein R²² is H or C₁₋₂alkyl; —C(O)OR²³ wherein R²³ is H or    C₁₋₂alkyl; —C(O)NHR²⁴ wherein R²⁴ is H or C₁₋₂alkyl; —C(O)R²⁵    wherein R²⁵ is C₁₋₂alkyl; fluoro; hydroxyimino (═N—OH); or    (C₁₋₄alkoxy)imino (═N—OR²⁶ where R²⁶ is C₁₋₄alkyl); and wherein any    OH, alkoxy, fluoroalkoxy or NHR²¹ substituent is not substituted at    the R³ ring carbon attached (bonded) to the —NH-group of formula (I)    and is not substituted at either R³ ring carbon bonded to the Y    group of the heterocyclic group (aa), (bb) or (cc);-   and wherein, when R³ is optionally substituted    mono-unsaturated-C₅₋₇cycloalkenyl, then the cycloalkenyl is    optionally substituted with one or two substituents being fluoro or    C₁₋₂alkyl provided that if there are two substituents then they are    not both C₂alkyl, and the R³ ring carbon bonded to the —NH— group of    formula (I) does not partake in the cycloalkenyl double bond;-   or R³ is a bicyclic group of sub-formula (dd):    or of sub-formula (ee):-   wherein Y¹, Y² and Y³ independently are CH₂ or oxygen (O) provided    that no more than one of Y¹, Y² and Y³ is oxygen (O);-   and X is NR⁴R⁵ or OR^(5a), in which:-   R⁴ is a hydrogen atom (H); C₁₋₆alkyl; C₁₋₃fluoroalkyl; or C₂₋₆alkyl    substituted by one substituent R¹¹; and-   R⁵ is a hydrogen atom (H); C₁₋₈alkyl; C₁₋₈ fluoroalkyl;    C₃₋₈cycloalkyl optionally substituted by a C₁₋₂alkyl group; or    —(CH₂)_(n) ⁴—C₃₋₈cycloalkyl optionally substituted, in the    —(CH₂)_(n) ⁴— moiety or in the C₃₋₈cycloalkyl moiety, by a C₁₋₂alkyl    group, wherein n⁴ is 1, 2 or 3;-   or R⁵ is C₂₋₆alkyl substituted by one or two independent    substituents R¹¹;-   wherein each substituent R¹¹, independently of any other R¹¹    substituent present, is: hydroxy (OH); C₁₋₆alkoxy; phenyloxy;    benzyloxy; —NR¹²R¹³; —NR¹⁵—C(O)R¹⁶; —NR¹⁵—C(O)—O—R¹⁶;    —NR¹⁵—C(O)—NH—R¹⁵; or —NR¹⁵—SO₂R¹⁶; and wherein any R¹¹ substituent    which is OH, alkoxy or —NR¹²R¹³ is not substituted at any carbon    atom, of any R⁴ or R⁵ substituted alkyl, which is bonded to the    nitrogen of NR⁴R⁵;-   or R⁵ is —(CH₂)_(n) ¹¹—C(O)R¹⁶; —(CH₂)_(n) ¹²—C(O)NR¹²R¹³;    —CHR¹⁹—C(O)NR¹²R¹³; —(CH₂)_(n) ¹²—C(O)OR¹⁶; —(CH₂)_(n) ¹²—C(O)OH;    —CHR¹⁹—C(O)OR¹⁶; —CHR¹⁹—C(O)OH; —(CH₂)_(n) ¹²—SO₂—NR¹²R¹³;    —(CH₂)_(n) ¹²—SO₂R¹⁶; or —(CH₂)_(n) ¹²—CN; wherein n¹¹ is 0, 1, 2, 3    or 4 and n¹² is 1, 2, 3 or 4;-   or R⁵ is —(CH₂)_(n) ¹³—Het wherein n¹³ is 0, 1, 2, 3 or 4 and Het is    a 4-, 5-, 6- or 7-membered saturated or partly-saturated    heterocyclic ring containing one or two ring-hetero-atoms    independently selected from O, S, and N; wherein any    ring-hetero-atoms present are not bound to the —(CH₂)_(n) ¹³— moiety    when n¹³ is 1 and are not bound to the nitrogen of NR⁴R⁵ when n¹³ is    0; wherein any ring-nitrogens which are present and which are not    unsaturated (i.e. which do not partake in a double bond) are present    as NR¹⁷ where R¹⁷ is as defined herein; and wherein one or two of    the carbon ring-atoms independently are optionally substituted by    C₁₋₂alkyl;-   or R⁵ is phenyl optionally substituted with, independently, one, two    or three of: a halogen atom; C₁₋₆alkyl (e.g. C₁₋₄alkyl or    C₁₋₂alkyl); C₁₋₂fluoroalkyl (e.g. trifluoromethyl); C₁₋₄alkoxy (e.g.    C₁₋₂alkoxy); C₁₋₂fluoroalkoxy (e.g. trifluoromethoxy);    C₃₋₆cycloalkyloxy; —C(O)R^(16a); —C(O)OR³⁰; —S(O)₂—R^(16a) (e.g.    C₁₋₂alkylsulphonyl or C₁₋₂alkyl-SO₂—); R^(16a)—S(O)₂—NR^(15a)— (e.g.    C₁₋₂alkyl-SO₂—NH—); R⁷R⁸N—S(O)₂—; C₁₋₂alkyl-C(O)—R^(15a)N—S(O)₂—;    C₁₋₄alkyl-S(O)—, Ph—S(O)—, R⁷R⁸N—CO—; —NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH;    C₁₋₄alkoxymethyl; C₁₋₄alkoxyethyl; C₁₋₂alkyl-S(O)₂—CH₂—;    R⁷R⁸N—S(O)₂—CH₂—; C₁₋₂alkyl-S(O)₂—NR^(15a)—CH₂—; —CH₂—OH;    —CH₂CH₂—OH; —CH₂—NR⁷R⁸; —CH₂—CH₂—NR⁷R⁸; —CH₂—C(O)OR³⁰;    —CH₂—C(O)—NR⁷R⁸; —CH₂—NR^(15a)—C(O)—C₁₋₃alkyl; —(CH₂)_(n) ¹⁴—Het¹    where n¹⁴ is 0 or 1; cyano (CN); Ar^(5a); or phenyl, pyridinyl or    pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl    independently are optionally substituted by one or two of fluoro,    chloro, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; or    where two adjacent substituents taken together are —O—(CMe₂)—O— or    O(CH₂)_(n) ¹⁴—O— where n¹⁴ is 1 or 2;    -   wherein R⁷ and R⁸ are independently a hydrogen atom (H);        C₁₋₄alkyl (e.g. C₁₋₂alkyl such as methyl); C₃₋₆cycloalkyl; or        phenyl optionally substituted by one or two of: fluoro, chloro,        C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; or R⁷        and R⁸ together are —(CH₂)_(n) ⁶— or —C(O)—(CH₂)_(n) ⁷— or        —C(O)—(CH₂)_(n) ⁷—C(O)— or —(CH₂)_(n) ⁸—X⁷—(CH₂)_(n) ⁹— or        —C(O)—X⁷—(CH₂)_(n) ¹⁰— in which: n⁶ is 3, 4, 5 or 6, n⁷ is 2, 3,        4, or 5 (preferably n⁷ is 2, 3 or 4), n⁸ and n⁹ and n¹⁰        independently are 2 or 3 (preferably independently 2), and X⁷ is        O or NR¹⁴ wherein R¹⁴ is H, C₁₋₂alkyl or C(O)Me (preferably H or        C₁₋₂alkyl);-   or R⁵ has the sub-formula (x), (y), (y1) or (z):-   wherein in sub-formula (x), n=0, 1 or 2; in sub-formula (y) and    (y1), m=1 or 2; and in sub-formula (z), r=0, 1 or 2;-   wherein in sub-formula (x) and (y) and (y1), none, one or two of A,    B, D, E and F are independently nitrogen or nitrogen-oxide (N⁺—O⁻)    provided that no more than one of A, B, D, E and F is    nitrogen-oxide; and the remaining of A, B, D, E and F are    independently CH or CR⁶;-   provided that when n is 0 in sub-formula (x) then one or two of A,    B, D, E and F are independently nitrogen or nitrogen-oxide (N⁺—O⁻)    and no more than one of A, B, D, E and F is nitrogen-oxide;-   wherein, each R⁶, independently of any other R⁶ present, is: a    halogen atom; C₁₋₆alkyl (e.g. C₁₋₄alkyl or C₁₋₂alkyl);    C₁₋₄fluoroalkyl (e.g. C₁₋₂fluoroalkyl); C₁₋₄alkoxy (e.g.    C₁₋₂alkoxy); C₁₋₂fluoroalkoxy; C₃₋₆cycloalkyloxy; —C(O)R^(16a);    —C(O)OR³⁰; —S(O)₂—R^(16a) (e.g. C₁₋₂alkylsulphonyl, that is    C₁₋₂alkyl-SO₂—); R^(16a)—S(O)₂—NR^(15a) (e.g. C₁₋₂alkyl-SO₂—NH—);    R⁷R⁸N—S(O)₂—; C₁₋₂alkyl-C(O)—R^(15a)N—S(O)₂—; C₁₋₄alkyl-S(O)—,    Ph—S(O)—, R⁷R⁸N—CO—; —NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH; C₁₋₄alkoxymethyl;    C₁₋₄alkoxyethyl; C₁₋₂alkyl-S(O)₂—CH₂—; R⁷R⁸N—S(O)₂—CH₂—;    C₁₋₂alkyl-S(O)₂—NR^(15a)—CH₂—; —CH₂—OH; —CH₂CH₂—OH; —CH₂—NR⁷R⁸;    —CH₂—CH₂—NR⁷R⁸; —CH₂—C(O)OR³⁰; —CH₂—C(O)—NR⁷R⁸;    —CH₂—NR^(15a)—C(O)—C₁₋₃alkyl; —(CH₂)_(n) ¹⁴—Het¹ where n¹⁴ is 0 or    1; cyano (CN); Ar^(5b); or phenyl, pyridinyl or pyrimidinyl wherein    the phenyl, pyridinyl or pyrimidinyl independently are optionally    substituted by one or two of fluoro, chloro, C₁₋₂alkyl,    C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; or where two adjacent    R⁶ taken together are —O—(CMe₂)—O— or —O—(CH₂)_(n) ¹⁴—O— where n¹⁴    is 1 or 2;-   wherein R⁷ and R⁸ are as herein defined;-   wherein sub-formula (y) and (y1), independently, are optionally    substituted by oxo (═O) at a ring carbon adjacent the 6-membered    aromatic ring (for example, sub-formula (y) can optionally be    or sub-formula (y1) can optionally be-   wherein in sub-formula (z), G is O or S or NR⁹ wherein R⁹ is a    hydrogen atom (H), C₁₋₄alkyl or C₁₋₄fluoroalkyl; none, one, two or    three of J, L, M and Q are nitrogen; and the remaining of J, L, M    and Q are independently CH or CR⁶ where R⁶, independently of any    other R⁶ present, is as defined herein;-   or R⁴ and R⁵ taken together are —(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²—    or —(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴— or —C(O)—X⁵—(CH₂)_(p) ⁵—, in which:    p¹=3, 4, 5 or 6 (preferably p=4 or 5), p² is 2, 3, 4, or 5    (preferably p² is 2, 3 or 4), and p³ and p⁴ and p⁵ independently are    2 or 3 (independently preferably 2) and X⁵ is O or NR¹⁷;    -   and wherein, when R⁴ and R⁵ taken together are —(CH₂)_(p) ¹— or        —C(O)—(CH₂)_(p) ²—, the NR⁴R⁵ heterocycle is optionally        substituted by one R¹⁸ substituent wherein R¹⁸ is: C₁₋₄alkyl        (e.g. C₁₋₂alkyl); C₁₋₂fluoroalkyl; C₃₋₆cycloalkyl; C₁₋₂alkoxy        (not substituted at a ring-carbon bonded to the NR⁴R⁵        ring-nitrogen); C₁fluoroalkoxy (not substituted at a ring-carbon        bonded to the NR⁴R⁵ ring-nitrogen); OH (not substituted at a        ring-carbon bonded to the NR⁴R⁵ ring-nitrogen); —(CH₂)_(p)        ⁷—C(O)R¹⁶ wherein p⁷ is 0, 1, 2 or 3 (preferably p⁷ is 0 or 1);        —(CH₂)_(p) ⁷—C(O)OR¹⁶; —(CH₂)_(p) ⁷—OC(O)R¹⁶; —(CH₂)_(p)        ⁷C(O)NR¹²R¹³; —(CH₂)_(p) ⁷—NR¹⁵C(O)R¹⁶; —(CH₂)_(p)        ⁷—NR¹⁵C(O)NR¹²R¹³; —(CH₂)_(p) ⁷—NR¹⁵C(O)OR¹⁶; —(CH₂)_(p)        ⁷—SO₂R¹⁶; —(CH₂)_(p) ⁷—SO₂ NR¹²R¹³; —(CH₂)_(p) ⁷—NR¹⁵SO₂R¹⁶;        —(CH₂)_(p) ⁷—OH; —(CH₂)_(p) ⁷—OR¹⁶; or phenyl optionally        substituted by one or two of: a halogen atom, C₁₋₂alkyl,        C₁fluoroalkyl, C₂alkoxy or C₁fluoroalkoxy;-   or R⁴ and R⁵ taken together are —(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²—    or —(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴— or —C(O)—X⁵—(CH₂)_(p) ⁵— as defined    herein, and wherein the NR⁴R⁵ heterocycle is fused to a phenyl ring    optionally substituted on the phenyl by one or two of: a halogen    atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; and-   R^(5a) is C₁₋₈alkyl; C₁₋₈ fluoroalkyl; C₃₋₈cycloalkyl; —(CH₂)_(n)    ^(4a)—C₃₋₆cycloalyl wherein n^(4a) is 1 or 2; phenyl optionally    substituted with one or two of: a halogen atom, C₁₋₂alkyl,    trifluoromethyl, C₁₋₂alkoxy or trifluoromethoxy; or R^(5a) has the    sub-formula (x), (y) or (z) as defined herein    and wherein:-   R¹² and R¹³ independently are H; C₁₋₅alkyl (e.g. C₁₋₃alkyl);    C₃₋₆cycloalkyl; or phenyl optionally substituted by one or two of: a    halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C    fluoroalkoxy;-   or R¹² and R¹³ together are —(CH₂)_(n) ⁶— or —C(O)—(CH₂)_(n) ⁷— or    —C(O)—(CH₂)_(n) ⁷—C(O)— or —(CH₂)_(n) ⁸—X¹²—(CH₂)_(n) ⁹— or    —C(O)—X¹²—(CH₂)_(n) ¹⁰— in which: n⁶ is 3, 4, 5 or 6 (preferably n⁶    is 4 or 5), n⁷ is 2, 3, 4, or 5 (preferably n⁷ is 2, 3 or 4), n⁸ and    n⁹ and n¹⁰ independently are 2 or 3 (independently preferably 2) and    X¹² is O or NR^(14a) wherein R^(14a) is H, C₁₋₂alkyl or C(O)Me    (preferably H or C₁₋₂alkyl);-   R¹⁵ is a hydrogen atom (H); C₁₋₄alkyl (e.g. tBu or C₁₋₂alkyl e.g.    methyl); C₃₋₆cycloalkyl; or phenyl optionally substituted by one or    two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁    fluoroalkoxy;-   R^(15a), independent of other R^(15a), is a hydrogen atom (H) or    C₁₋₄alkyl (e.g. H, tBu or C₁₋₂alkyl such as methyl; preferably    R^(15a) is H or C₁₋₂alkyl, more preferably H);-   R¹⁶ and R^(16a) independently are:    -   C₁₋₆alkyl (e.g. C₁₋₄alkyl or C₁₋₂alkyl);    -   C₃₋₆cycloalkyl (e.g. C₅₋₆cycloalkyl) optionally substituted by        one oxo (═O), OH or C₁₋₂alkyl substituent (e.g. optionally        substituted at the 3- or 4-position of a C₅₋₆cycloalkyl ring;        and/or preferably unsubstituted C₃₋₆cycloalkyl);    -   C₃₋₆cycloalkyl-CH₂— (e.g. C₅₋₆cycloalkyl-CH₂—);    -   pyridinyl (e.g. pyridin-2-yl) optionally substituted on a ring        carbon atom by one of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl,        C₁₋₂alkoxy or C₁fluoroalkoxy;    -   Ar^(5c);    -   phenyl optionally substituted by one or two of: a halogen atom,        C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy;    -   benzyl optionally substituted at an aromatic carbon atom by one        or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy        or C₁fluoroalkoxy; or    -   a 4-, 5-, 6- or 7-membered saturated heterocyclic ring connected        at a ring-carbon and containing one or two ring-hetero-atoms        independently selected from O, S, and N;-   wherein any ring-nitrogens which are present are present as NR²⁷    where R²⁷ is H, C₁₋₂alkyl or —C(O)Me; and wherein the ring is    optionally substituted at carbon by one C₁₋₂alkyl or oxo (═O)    substituent, provided that any oxo (═O) substituent is substituted    at a ring-carbon atom bonded to a ring-nitrogen;-   wherein Ar^(5a), Ar^(5b) and Ar^(5c) independently is/are a    5-membered aromatic heterocyclic ring containing one O, S or    NR^(15a) in the 5-membered ring, wherein the 5-membered ring can    optionally additionally contain one or two N atoms, and wherein the    heterocyclic ring is optionally substituted on a ring carbon atom by    one of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, —CH₂OH,    —CH₂—OC₁₋₂alkyl, OH (including the keto tautomer thereof) or    —CH₂—NR²⁸R²⁹ wherein R²⁸ and R²⁹ independently are H or methyl;-   and R¹⁷ is a hydrogen atom (H); C₁₋₄alkyl (e.g. C₁₋₂alkyl);    C₁₋₂fluoroalkyl; C₃₋₆cycloalkyl; —(CH₂)_(p) ⁶—C(O)R¹⁶ wherein p⁶ is    0, 1, 2 or 3 (preferably p⁶ is 0); —(CH₂)_(p) ⁶—C(O)NR¹²R¹³;    —(CH₂)_(p) ⁶—C(O)OR¹⁶; —(CH₂)_(p) ⁶—C(O)OH; —SO₂R¹⁶;    —C(O)—CH₂—NR¹²R¹³; —C(O)—CH₂—NR^(15a)—C(O)—C₁₋₃alkyl;    —C(O)—CH₂—O—C₁₋₃alkyl; or phenyl or benzyl wherein the phenyl or    benzyl is optionally substituted at an aromatic carbon atom by one    or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or    C₁fluoroalkoxy;-   R¹⁹ is C₁₋₄alkyl; —(CH₂)_(n) ²⁰—OR²⁰ wherein n²⁰ is 1, 2, 3 or 4 and    R²⁰ is a hydrogen atom (H) or C₁₋₄alkyl; —CH(Me)-OH; —CH₂—SH;    —CH₂—CH₂—S-Me; benzyl; or (4-hydroxyphenyl)methyl (i.e.    4-hydroxy-benzyl); and-   R³⁰, independent of other R³⁰, is a hydrogen atom (H), C₁₋₄alkyl or    C₃₋₆cycloalkyl; and-   Het¹, independent of other Het¹, is a 4-, 5-, 6- or 7-membered    saturated heterocyclic ring connected at a ring-carbon and    containing one or two ring-hetero-atoms independently selected from    O, S, and N; wherein any ring-nitrogens which are present are    present as NR³¹ where R³¹ is H, C₁₋₂alkyl or —C(O)Me; and wherein    the ring is optionally substituted at carbon by one C₁₋₂alkyl or oxo    (═O) substituent, provided that any oxo (═O) substituent is    substituted at a ring-carbon atom bonded to a ring-nitrogen;    provided that:-   when R³ is the heterocyclic group of sub-formula (bb), n¹ is 1, and    Y is NR¹⁰, then:-   either (a) R¹⁰ is not C₁₋₄alkyl, C₁₋₂fluoroalkyl or CH₂C(O)NH₂;-   or (b) R¹⁰ is methyl and the compound is:    1-ethyl-N-(2-ethylbutyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide    or    1-ethyl-N-(4-fluorophenyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide.

Preferably, where X is OR^(5a), the compound is other than the compoundwherein R¹ is methyl, X is OEt, and R³ is cyclopentyl.

In one optional embodiment of the invention, R¹ is C₁₋₄alkyl orC₁₋₂fluoroalkyl.

Alternatively or additionally, in one optional embodiment of theinvention, R² is a hydrogen atom (O).

Alternatively or additionally, in one optional embodiment of theinvention, R³ is C₃₋₈cycloalkyl or a heterocyclic group being

-   in which Y is O, S, SO₂, or NR¹⁰; where R¹⁰ is hydrogen, C₁₋₄alkyl,    C₁₋₂fluoroalkyl, C(O)—C₁₋₂alkyl, or C(O)—CF₃;-   and wherein in R³ the C₃₋₈cycloalkyl or heterocyclic group is    optionally substituted with one or two substituents being OH,    C₁₋₂alkoxy, trimethoxy, or C₁₋₂alkyl; and wherein any OH, alkoxy or    trimethoxy substituent is not substituted at the (R³) ring carbon    attached (bonded) to the —NH— group of formula (I) and is not    substituted at either (R³) ring carbon bonded to the Y group of the    heterocyclic group.

Alternatively or additionally, in one optional embodiment of theinvention, R⁴ is hydrogen, C₁₋₂alkyl or C₁₋₂fluoroalkyl.

Alternatively or additionally, in one optional embodiment of theinvention, R⁵ is hydrogen, C₁₋₈alkyl, C₁₋₈ fluoroalkyl, orC₃₋₈cycloalkyl; or phenyl optionally substituted with one or two of: ahalogen atom, C₁₋₂alkyl, trifluoromethyl, C₁₋₂alkoxy ortrifluoromethoxy; or R⁵ has the sub-formula (x), (y) or (z):

-   -   wherein in sub-formula (x), n=1 or 2; in sub-formula (y), m=1 or        2; and in sub-formula (z), r=1 or 2;    -   wherein in sub-formula (x) and (y), none, one or two of A, B, D,        E and F are nitrogen; and the remaining of A, B, D, E and F are        CH or CR⁶ where R⁶ is a halogen atom, C₁₋₄alkyl,        C₁₋₄fluoroalkyl, C₁₋₂alkoxy, C₁₋₂fluoroalkoxy,        C₁₋₂alkylsulphonyl (C₁₋₂alkyl-SO₂—), C₁₋₂alkyl-SO₂—NH—,        R⁷R⁸N—SO₂—, R⁷R⁸N—CO—, R⁷R⁸N, OH, C₁₋₄alkoxymethyl, or        C₁₋₂alkyl-SO₂—CH₂—, wherein R⁷ and R⁸ are independently hydrogen        or C₁₋₂alkyl;    -   wherein in sub-formula (z), G is O or S or NR⁹ wherein R⁹ is        C₁₋₄alkyl or C₁₋₄fluoroalkyl; none, one or two of J, L, M and Q        are nitrogen; and the remaining of J, L, M and Q are CH or CR⁶        where R⁶ is as defined herein.

In the alternative to the above R⁴ and/or R⁵ optional embodiments, inone optional embodiment of the invention, R⁴ and R⁵ taken together canbe ——(CH₂)_(p) ¹— where p¹=3, 4 or 5 (preferably p¹=4 or 5).

In one optional embodiment of the invention, R³ is optionallysubstituted C₃₋₈cycloalkyl or an optionally substituted heterocyclicgroup of sub-formula (aa), (bb) or (cc);

-   in which n¹ and n² independently are 1 or 2; and in which Y is O, S,    SO₂, or NR¹⁰; where R¹⁰ is a hydrogen atom (H), C₁₋₄alkyl (e.g.    methyl or ethyl), C₁₋₂fluoroalkyl, CH₂C(O)NH₂, C(O)NH₂,    C(O)—C₁₋₂alkyl, or C(O)—C₁fluoroalkyl;    -   and wherein in R³ the C₃₋₈cycloalkyl or the heterocyclic group        of sub-formula (aa), (bb) or (cc) is optionally substituted with        one or two substituents being oxo (═O), OH, C₁₋₂alkoxy,        C₁₋₂fluoroalkoxy (e.g. trifluoromethoxy), or C₁₋₂alkyl; and        wherein any OH, alkoxy or fluoroalkoxy substituent is not        substituted at the R³ ring carbon attached (bonded) to the —NH—        group of formula (I) and is not substituted at either R³ ring        carbon bonded to the Y group of the heterocyclic group (aa),        (bb) or (cc).

Alternatively or additionally to the above optional R³ definition, inone optional embodiment of the invention, X is NR⁴R⁵ or OR^(5a), inwhich:

-   R⁴ is a hydrogen atom (H); C₁₋₆alkyl; C₁₋₃fluoroalkyl; or C₂₋₆alkyl    substituted by one substituent R¹¹; and-   R⁵ is a hydrogen atom (H); C₁₋₈alkyl; C₁₋₈ fluoroalkyl;    C₃₋₈cycloalkyl optionally substituted by a C₁₋₂alkyl group; or    —(CH₂)_(n) ⁴—C₃₋₈cycloalkyl optionally substituted, in the    —(CH₂)_(n) ⁴— moiety or in the C₃₋₈cycloalkyl moiety, by a C₁₋₂alkyl    group, wherein n⁴ is 1, 2 or 3;-   or R⁵ is C₂₋₆alkyl substituted by one or two independent    substituents R¹¹;-   wherein each substituent R¹¹, independently of any other R¹¹    substituent present, is: hydroxy (OH); C₁₋₆alkoxy; phenyloxy;    benzyloxy; —NR¹²R¹³; —NR¹⁵—C(O)R¹⁶; —NR¹⁵—C(O)—O—R¹⁶;    —NR¹⁵—C(O)—NH—R¹⁵; or —NR¹⁵—SO₂R¹⁶; and wherein any R¹¹ substituent    which is OH, alkoxy or —NR¹²R¹³ is not substituted at any carbon    atom, of any R⁴ or R⁵ substituted alkyl, which is bonded to the    nitrogen of NR⁴R⁵;-   or R⁵ is —(CH₂)_(n) ¹¹—C(O)R¹⁶; —(CH₂)_(n) ¹²—C(O)NR¹²R¹³;    —CHR¹⁹—C(O)NR¹²R¹³; —(CH₂)_(n) ¹²—C(O)OR¹⁶; —CHR¹⁹—C(O)OR¹⁶;    —(CH₂)_(n) ¹¹²—SO₂—NR¹²R¹³; —(CH₂)_(n) ¹²—SO₂R¹⁶; or —(CH₂)_(n)    ¹²—CN; wherein n¹¹ is 0, 1, 2, 3 or 4 and n¹² is 1, 2, 3 or 4;-   or R⁵ is —(CH₂)_(n) ¹³-Het wherein n¹³ is 0, 1, 2, 3 or 4 and Het is    a 4-, 5-, 6- or 7-membered saturated or partly-saturated    heterocyclic ring containing one or two ring-hetero-atoms    independently selected from O, S, and N; wherein any    ring-hetero-atoms present are not bound to the —(CH₂)_(n) ¹³-moiety    when n¹³ is 1 and are not bound to the nitrogen of NR⁴R⁵ when n¹³ is    0; wherein any ring-nitrogens which are present and which are not    unsaturated (i.e. which do not partake in a double bond) are present    as NR¹⁷ where R¹⁷ is as defined herein; and wherein one or two of    the carbon ring-atoms independently are optionally substituted by    C₁₋₂alkyl;-   or R⁵ is phenyl optionally substituted with one or two of: a halogen    atom; C₁₋₄alkyl (e.g. C₁₋₂alkyl); C₁₋₂fluoroalkyl (e.g.    trifluoromethyl); C₁₋₄alkoxy (e.g. C₁₋₂alkoxy); C₁₋₂fluoroalkoxy    (e.g. trifluoromethoxy); C₁₋₂alkylsulphonyl (C₁₋₂alkyl-SO₂—);    C₁₋₂alkyl-SO₂—NH—; R⁷R⁸N—SO₂—; R⁷R⁸N—CO—; —NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH;    C₁₋₄alkoxymethyl; C₁₋₄alkoxyethyl; C₁₋₂alkyl-SO₂—CH₂—; cyano (CN);    or phenyl optionally substituted by one or two of fluoro, chloro,    C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy;    -   wherein R⁷ and R⁸ are independently a hydrogen atom (E);        C₁₋₄alkyl (e.g. C₁₋₂alkyl such as methyl); C₃₋₆cycloalkyl; or        phenyl optionally substituted by one or two of: fluoro, chloro,        C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy, or R⁷        and R⁸ together are —(CH₂)_(n) ⁶— or —C(O)—(CH₂)_(n) ⁷— or        —C(O)—(CH₂)_(n) ⁷—C(O)— or —(CH₂)_(n) ⁸—X⁷—(CH₂)_(n) ⁹— or        —C(O)—X⁷—(CH₂)_(n) ¹⁰ in which: n⁶ is 3, 4, 5 or 6, n⁷ is 2, 3,        4, or 5 (preferably n⁷ is 2, 3 or 4), n⁸ and n⁹ and n¹⁰        independently are 2 or 3, and X⁷ is O or NR¹⁴ wherein R¹⁴ is H        or C₁₋₂alkyl;-   or R⁵ has the sub-formula (x), (y) or (z):-   wherein in sub-formula (x), n=1 or 2; in sub-formula (y), m=1 or 2;    and in sub-formula (z), r=0, 1 or 2;-   wherein in sub-formula (x) and (y), none, one or two of A, B, D, E    and F are nitrogen; and the remaining of A, B, D, E and F are    independently CH or CR⁶;-   where R⁶ is a halogen atom; C₁₋₄alkyl (e.g. C₁₋₂alkyl);    C₁₋₄fluoroalkyl (e.g. C₁₋₂fluoroalkyl); C₁₋₄alkoxy (e.g.    C₁₋₂alkoxy); C₁₋₂fluoroalkoxy; C₁₋₂alkylsulphonyl (C₁₋₂alkyl-SO₂—);    C₁₋₂alkyl-SO₂—NH—; R⁷R⁸N—SO₂—; R⁷R⁸N—CO—; —NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH;    C₁₋₄alkoxymethyl; C₁₋₄alkoxyethyl; C₁₋₂alkyl-SO₂—CH₂—; cyano (CN);    or phenyl optionally substituted by one or two of fluoro, chloro,    C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; wherein R⁷    and R⁸ are as herein defined;-   wherein in sub-formula (z), G is O or S or NR⁹ wherein R⁹ is a    hydrogen atom (H), C₁₋₄alkyl or C₁₋₄fluoroalkyl; none, one, two or    three of J, L, M and Q are nitrogen; and the remaining of J, L, M    and Q are independently CH or CR⁶ where R⁶ is as defined herein;-   or R⁴ and R⁵ taken together are ——(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²—    or —(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴— or —C(O)—X⁵—(CH₂)_(p) ⁵—, in which:    p¹=3, 4, 5 or 6 (preferably p=4 or 5), p² is 2, 3, 4, or 5    (preferably p² is 2, 3 or 4), and p³ and p⁴ and p⁵ independently are    2 or 3 (independently preferably 2) and X⁵ is O or NR¹⁷;    -   wherein R¹⁷ is a hydrogen atom (H); C₁₋₄alkyl (e.g. C₁₋₂alkyl);        C₁₋₂fluoroalkyl; C₃₋₆cycloalkyl; —(CH₂)_(p) ⁶—C(O)R¹⁶ wherein p⁶        is 0, 1, 2 or 3 (preferably p⁶ is 0); —(CH₂) 6—C(O)NR¹²R¹³;        —(CH₂)_(p) ⁶—C(O)OR¹⁶; —SO₂R¹⁶; or phenyl or benzyl wherein the        phenyl or benzyl is optionally substituted at an aromatic carbon        atom by one or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl,        C₁₋₂alkoxy or C₁fluoroalkoxy,    -   and wherein, when R⁴ and R⁵ taken together are —(CH₂)_(p) ¹— or        —C(O)—(CH₂)_(p) ²—, the NR⁴R⁵ heterocycle is optionally        substituted by one R¹⁸ substituent wherein R¹⁸ is: C₁₋₄alkyl        (e.g. C₁₋₂alkyl); C₁₋₂fluoroalkyl; C₃₋₆cycloalkyl; C₁₋₂alkoxy        (not substituted at a ring-carbon bonded to the NR⁴R⁵        ring-nitrogen); C₁fluoroalkoxy (not substituted at a ring-carbon        bonded to the NR⁴R⁵ ring-nitrogen); OH (not substituted at a        ring-carbon bonded to the NR⁴R⁵ ring-nitrogen); —(CH₂)_(p)        ⁷—C(O)R¹⁶ wherein p⁷ is 0, 1, 2 or 3 (preferably p⁷ is 0 or 1);        —(CH₂)_(p) ⁷—C(O)OR¹⁶; —(CH₂)_(p) ⁷—OC(O)R¹⁶; —(CH₂)_(p)        ⁷—C(O)NR¹²R¹³; —(CH₂)_(p) ⁷—NR¹⁵C(O)R¹⁶; —(CH₂)_(p)        ⁷—NR¹⁵C(O)NR¹²R¹³; —(CH₂)_(p) ⁷—NR¹⁵C(O)OR¹⁶; —(CH₂)_(p)        ⁷—SO₂R¹⁶; —(CH₂)_(p) ⁷—SO₂ NR¹²R¹³; —(CH₂)_(p) ⁷—NR¹⁵SO₂R¹⁶;        —(CH₂)_(p) ⁷—OH; —(CH₂)_(p) ⁷—OR¹⁶; or phenyl optionally        substituted by one or two of: a halogen atom, C₁₋₂alkyl,        C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy;-   or R⁴ and R⁵ taken together are ——(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²—    or —(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴— or —C(O)—X⁵—(CH₂)_(p) ⁵— as defined    herein, and wherein the NR⁴R⁵ heterocycle is fused to a phenyl ring    optionally substituted on the phenyl by one or two of: a halogen    atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C fluoroalkoxy; and-   R^(5a) is C₁₋₈alkyl; C₁₋₈ fluoroalkyl; C₃₋₈cycloalkyl; phenyl    optionally substituted with one or two of: a halogen atom,    C₁₋₂alkyl, trifluoromethyl, C₁₋₂alkoxy or trifluoromethoxy; or    R^(5a) has the sub-formula (x), (y) or (z) as defined herein    and wherein:-   R¹² and R¹³ independently are H; C₁₋₅alkyl (e.g. C₁₋₃alkyl);    C₃₋₆cycloalkyl; or phenyl optionally substituted by one or two of: a    halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or    C₁fluoroalkoxy;-   or R¹² and R¹³ together are —(CH₂)_(n) ⁶— or —C(O)—(CH₂)_(n) ⁷— or    —C(O)—(CH₂)_(n) ⁷—C(O)— or —(CH₂)_(n) ⁸—X¹²—(CH₂)_(n) ⁹— or    —C(O)—X¹²—(CH₂)_(n) ¹⁰— in which: n⁶ is 3, 4, 5 or 6 (preferably n⁶    is 4 or 5), n⁷ is 2, 3, 4, or 5 (preferably n⁷ is 2, 3 or 4), n⁸ and    n⁹ and n¹⁰ independently are 2 or 3 (independently preferably 2) and    X¹² is O or NR¹⁴ wherein-   R¹⁴ is H or C₁₋₂alkyl;-   R¹⁵ is a hydrogen atom (H); C₁₋₄alkyl (e.g. tBu or C₁₋₂alkyl e.g.    methyl); C₃₋₆cycloalkyl; or phenyl optionally substituted by one or    two of: a halogen atom, C₁₋₂alkyl, C₁ fluoroalkyl, C₁₋₂alkoxy or C₁    fluoroalkoxy;-   R¹⁶ is C₁₋₄alkyl (e.g. C₁₋₂alkyl); C₃₋₆cycloalkyl; pyridinyl (e.g.    pyridin-2-yl); or phenyl optionally substituted by one or two of: a    halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or    C₁fluoroalkoxy; and-   R¹⁹ is C₁₋₄alkyl; —(CH₂)_(n) ²⁰—OR²⁰ wherein n²⁰ is 1, 2, 3 or 4 and    R²⁰ is a hydrogen atom (H) or C₁₋₄alkyl; —CH(Me)-OH; —CH₂—SH;    —CH₂—CH₂—S-Me; benzyl; or (4-hydroxyphenyl)methyl (i.e.    4-hydroxy-benzyl).

In compounds, for example in the compounds of formula (I) (or formula(IA) or formula (IB), see later), an “alkyl” group or moiety may bestraight-chain or branched. Alkyl groups, for example C₁₋₈alkyl orC₁₋₆alkyl or C₁₋₄alkyl or C₁₋₃alkyl or C₁₋₂alkyl, which may be employedinclude C₁₋₆alkyl or C₁₋₄alkyl or C₁₋₃alkyl or C₁₋₂alkyl such as methyl,ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl or any branched isomersthereof such as isopropyl, t-butyl, sec-butyl, isobutyl,3-methylbutan-2-yl, 2-ethylbutan-1-yl, or the like.

A corresponding meaning is intended for “alkoxy”, “alkylene”, and liketerms derived from alkyl. For example, “alkoxy” such as C₁₋₆alkoxy orC₁₋₄alkoxy or C₁₋₂alkoxy includes methoxy, ethoxy, propyloxy, and oxyderivatives of the alkyls listed above. “Alkylsulfonyl” such asC₁₋₄alkylsulfonyl includes methylsulfonyl (methanesulfonyl),ethylsulfonyl, and others derived from the alkyls listed above.“Alkylsulfonyloxy” such as C₁₋₄alkylsulfonyloxy includesmethanesulfonyloxy (methylsulfonyloxy), ethanesulfonyloxy, et al.

“Cycloalkyl”, for example C₃₋₈cycloalkyl, includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and thelike. Preferably, a C₃₋₈cycloalkyl group is C₃₋₆cycloalkyl orC₅₋₆cycloalkyl, that is contains a 3-6 membered or 5-6 memberedcarbocyclic ring.

“Fluoroalkyl” includes alkyl groups with one, two, three, four, five ormore fluorine substituents, for example C₁₋₄fluoroalkyl orC₁₋₃fluoroalkyl or C₁₋₂fluoroalkyl such as monofluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl(CF₃CH₂—), 2,2-difluoroethyl (CHF₂CH₂—), 2-fluoroethyl (CH₂FCH₂—), etc.“Fluoroalkoxy” includes C₁₋₄fluoroalkoxy or C₁₋₂fluoroalkoxy such astrifluoromethoxy, pentafluoroethoxy, monofluoromethoxy, difluoromethoxy,etc. “Fluoroalkylsulfonyl” such as C₁₋₄fluoroalkylsulfonyl includestrifluoromethanesulfonyl, pentafluoroethylsulfonyl, etc.

A halogen atom (“halo”) present in compounds, for example in thecompounds of formula (I), can be a fluorine, chlorine, bromine or iodineatom (“fluoro”, “chloro”, “bromo” or “iodo”).

When the specification states that atom or moiety A is “bonded” or“attached” to atom or moiety B, it means that atom/moiety A is directlybonded to atom/moiety B usually by means of one or more covalent bonds,and excludes A being indirectly attached to B via one or moreintermediate atoms/moieties (e.g. excludes A-C-B); unless it is clearfrom the context that another meaning is intended.

Preferably, R¹ is C₁₋₄alkyl (e.g. methyl, ethyl, n-propyl, isopropyl orn-butyl), C₁₋₃fluoroalkyl or —CH₂CH₂OH; R¹ is more preferably C₁₋₃alkyl(e.g. methyl, ethyl or n-propyl), C₁₋₂fluoroalkyl, or —CH₂CH₂OH; stillmore preferably C₁₋₃alkyl, C₂fluoroalkyl or —CH₂CH₂OH such as methyl,ethyl, n-propyl or —CH₂CH₂OH. Yet more preferably, R¹ is C₂₋₃alkyl (e.g.ethyl or n-propyl), C₂fluoroalkyl (e.g. C₁fluoroalkyl-CH₂— such asCF₃—CH₂—) or —CH₂CH₂OH; in particular ethyl, n-propyl or —CH₂CH₂OH. R¹is most preferably ethyl.

Preferably, R² is a hydrogen atom (H) or methyl, more preferably ahydrogen atom (H).

Preferably, in R³ there is one substituent or no substituent.

In one optional embodiment, R³ is the optionally substitutedC₃₋₈cycloalkyl or the optionally substituted heterocyclic group ofsub-formula (aa), (bb) or (cc). In this embodiment, optionally, in R³,the C₃₋₈cycloalkyl or the heterocyclic group of sub-formula (aa), (bb)or (cc) is optionally substituted with one or two substituentsindependently being (e.g. being) oxo (═O), OH, C₁₋₂alkoxy,C₁₋₂fluoroalkoxy (e.g. trifluoromethoxy), or C₁₋₂alkyl; and wherein anyOH, alkoxy or fluoroalkoxy substituent is not substituted at the R³ ringcarbon attached (bonded) to the —NH— group of formula (I) and is notsubstituted at either R³ ring carbon bonded to the Y group of theheterocyclic group (aa), (bb) or (cc).

In one optional embodiment, where R³ is optionally substitutedC₃₋₈cycloalkyl, it is not optionally substituted C₅cycloalkyl, i.e. notoptionally substituted cyclopentyl. In this case, more preferably, R³ isoptionally substituted C₆₋₈cycloalkyl.

Where R³ is optionally substituted C₃₋₈cycloalkyl, it is more preferablyoptionally substituted C₆cycloalkyl (i.e. cyclohexyl); for exampleC₆cycloalkyl optionally substituted with one or two substituentsindependently being (e.g. being) oxo (═O), OH, C₁₋₂alkoxy,C₂fluoroalkoxy (e.g. trifluoromethoxy), or C₁₋₂alkyl, and wherein anyOH, alkoxy or fluoroalkoxy substituent is not substituted at the R³ ringcarbon attached (bonded) to the —NH— group of formula (I).

Where R³ is optionally substituted C₃₋₈cycloalkyl, the one or twooptional substituents preferably comprise (e.g. is or independently are(e.g. is or are)) oxo (═O); OH; C₁alkoxy; C₁fluoroalkoxy (e.g.trifluoromethoxy); NHR²¹ wherein R²¹ is a hydrogen atom (H) or C₁₋₂straight-chain alkyl; C₁₋₂alkyl such as methyl; C₁fluoroalkyl such as—CH₂F or —CHF₂; —CH₂OH; —CH₂NHR²² wherein R²² is H; —C(O)OR²³ whereinR²³ is H or methyl; —C(O)NHR²⁴ wherein R²⁴ is H or methyl; —C(O)R²⁵wherein R²⁵ is methyl; fluoro; hydroxyimino (═N—OH); or(C₁₋₂alkoxy)imino (═N—OR²⁶ where R²⁶ is C₁₋₂alkyl); and wherein any OH,alkoxy, fluoroalkoxy or NHR²¹ substituent is not substituted at the R³ring carbon attached (bonded) to the —NH— group of formula (I) and isnot substituted at either R³ ring carbon bonded to the Y group of theheterocyclic group (aa), (bb) or (cc).

More preferably, where R³ is optionally substituted C₃₋₈cycloalkyl, theone or two optional substituents comprise (e.g. is or independently are(e.g. is or are)) oxo (═O); OH; NHR²¹ wherein R²¹ is a hydrogen atom(H); C₁₋₂alkyl such as methyl; C₁fluoroalkyl such as —CH₂F or —CHF₂;—C(O)OR²³ wherein R²³ is H or methyl; —C(O)NHR²⁴ wherein R²⁴ is H ormethyl; fluoro; hydroxyimino (═N—OH); or (C₁₋₂alkoxy)imino (═N—OR²⁶where R²⁶ is C₁₋₂alkyl).

Still more preferably, where R³ is optionally substitutedC₃₋₈cycloalkyl, the one or two optional substituents comprise (e.g. isor independently are (e.g. is or are)) oxo (═O); OH; NHR²¹ wherein R²¹is a hydrogen atom (H); methyl; —CH₂F; —CHF₂; —C(O)OR²³ wherein R²³ isH; fluoro; hydroxyimino (═N—OH); or (C₁₋₂alkoxy)imino (═N—OR²⁶ where R²⁶is C₁₋₂alkyl). Yet more preferably, where R³ is optionally substitutedC₃₋₈cycloalkyl, the one or two optional substituents comprise (e.g. isor independently are (e.g. is or are)) oxo (═O); OH; methyl; fluoro;hydroxyimino (═N—OH); or (C₁₋₂alkoxy)imino (═N—OR²⁶ where R²⁶ isC₁₋₂alkyl).

Most preferably, where R³ is optionally substituted C₃₋₈cycloalkyl, theone or two optional substituents comprise (e.g. is or independently are(e.g. is or are)) OH, oxo (═O) or oximo (═N—OH). For example, the one ortwo optional substituents can comprise (e.g. is or are) OH and/or oxo(═O).

Optionally, in R³, the C₃₋₈cycloalkyl can be unsubstituted.

Where R³ is optionally substituted C₃₋₈cycloalkyl, e.g. optionallysubstituted C₅₋₈cycloalkyl such as optionally substituted C₆cycloalkyl(optionally substituted cyclohexyl), the one or two optionalsubstituents if present preferably comprise a substituent (for exampleis or are substituent(s)) at the 3-, 4- or 5-position(s) of the R³cycloalkyl ring. (In this connection, the 1-position of the R³cycloalkyl ring is deemed to be the connection point to the —NH— informula (I)).

Where R³ is optionally substituted C₃₋₈cycloalkyl, any OH, alkoxy,fluoroalkoxy, —CH₂OH, —CH₂CH₂OH, —CH₂NHR²², —C(O)OR²³, —C(O)NHR²⁴,—C(O)R²⁵ or fluoro substituent (particularly any OH substituent) is morepreferably at the the 3-, 4- or 5-position, e.g. 3- or 5-position, ofthe R³ cycloalkyl (e.g. C₆₋₈cycloalkyl) ring. For example, any OH,alkoxy, fluoroalkoxy, —CH₂OH, —CH₂CH₂OH, —CH₂NHR²², —C(O)OR²³,—C(O)NHR²⁴, —C(O)R²⁵ or fluoro substituent (particularly any OHsubstituent) can be at the 3-position of a R³ C₅cycloalkyl (cyclopentyl)ring or at the 3-, 4- or 5-position, e.g. 3- or 5-position, of a R³C₆cycloalkyl (cyclohexyl) ring. (In this connection, and also below, the1-position of the R³ cycloalkyl ring is deemed to be the connectionpoint to the —NH— in formula (I)).

Where R³ is optionally substituted C₃₋₈cycloalkyl, any NHR²¹ substituentis preferably at the 2-, 3-, 4- or 5-position, preferably the 2- or3-position or more preferably the 3-position, of the R³ cycloalkyl (e.g.C₆₋₈cycloalkyl e.g. cyclohexyl) ring.

Where R³ is optionally substituted C₃₋₈cycloalkyl, any alkyl orfluoroalkyl substituent is preferably at the 1-, 2-, 3-, 4- or5-position, more preferably the 1-, 2-, 3- or 5-position, still morepreferably the 1- or 3-position, of the R³ cycloalkyl (e.g.C₆₋₈cycloalkyl e.g. cyclohexyl) ring.

Where R³ is optionally substituted C₃₋₈cycloalkyl, any oxo (═O),hydroxyimino (═N—OH); or (C₁₋₄alkoxy)imino (═N—OR²⁶) substituent ispreferably at the 3- or 4-position, preferably at the 4-position, of theR³ cycloalkyl (e.g. C₆₋₈cycloalkyl e.g. cyclohexyl) ring.

Where R³ is optionally substituted C₃₋₈cycloalkyl, R³ is preferablycyclohexyl (i.e. unsubstituted), or cyclohexyl substituted by one oxo(═O), OH, NHR²¹, C₁₋₂alkyl, C₁₋₂fluoroalkyl, —CH₂OH, —C(O)OR²³,—C(O)NHR²⁴, —C(O)R²⁵, fluoro, hydroxyimino (═N—OH), (C₁₋₄alkoxy)imino(═N—OR²⁶) substituent, or cyclohexyl substituted by two fluorosubstituents. More preferably, R³ is cyclohexyl (i.e. unsubstituted), orcyclohexyl substituted by one oxo (═O), OH, NHR²¹, C₁₋₂alkyl,C₁₋₂fluoroalkyl, —C(O)OR²³, fluoro, hydroxyimino (═N—OH) or(C₁₋₄alkoxy)imino (═N—OR²⁶) substituent, or cyclohexyl substituted bytwo fluoro substituents. Still more preferably R³ is cyclohexyl (i.e.unsubstituted) or cyclohexyl substituted by one oxo (═O), hydroxyimino(═N—OH), C₁₋₂alkyl or OH substituent. The optional substituent can be atthe 3- or 4-position, e.g. 3-position, of the R³ cyclohexyl ring; morepreferably any OH substituent is preferably at the 3-position of the R³cyclohexyl ring, and/or any oxo (═O), hydroxyimino (═N—OH) or(C₁₋₄alkoxy)imino (═N—OR²⁶) substituent is preferably at the 4-positionof the R³ cyclohexyl ring.

Where R³ is optionally substituted C₆cycloalkyl, R³ can for example be4-hydroxy-cyclohexyl (i.e. 4-hydroxycyclohexan-1-yl), but R³ is morepreferably cyclohexyl (i.e. unsubstituted), 3-hydroxy-cyclohexyl (i.e.3-hydroxycyclohexan-1-yl), 4-oxo-cyclohexyl (i.e. 4-oxocyclohexan-1-yl),4-(hydroxyimino)cyclohexyl (i.e. 4-(hydroxyimino)cyclohexan-1-yl),4-(C₁₋₂alkoxyimino)cyclohexyl, 1-methylcyclohexyl or 3-methylcyclohexyl.Where R³ is optionally substituted C₆cycloalkyl, R³ is most preferablycyclohexyl (i.e. unsubstituted), 4-oxo-cyclohexyl (i.e.4-oxocyclohexan-1-yl) or 4-(hydroxyimino)cyclohexyl (i.e.4-(hydroxyimino)cyclohexan-1-yl).

Where R³ is optionally substituted C₅cycloalkyl (optionally substitutedcyclopentyl), R³ can for example be cyclopentyl (i.e. unsubstituted) or3-hydroxy-cyclopentyl.

Where R³ is optionally substituted mono-unsaturated-C₅₋₇cycloalkenyl,preferably it is optionally substitutedmono-unsaturated-C₅₋₆cycloalkenyl, more preferably optionallysubstituted mono-unsaturated-C₆cycloalkenyl (i.e. optionally substitutedmono-unsaturated-cyclohexenyl=optionally substituted cyclohexenyl).Still more preferably, the R³ cyclohexenyl is optionally substitutedcyclohex-3-en-1-yl.

Where R³ is optionally substituted mono-unsaturated-C₅₋₇cycloalkenyl,preferably the R³ cycloalkenyl is optionally substituted with one or twosubstituents being fluoro or methyl provided that if there are twosubstituents then they are not both methyl. Preferably, the R³cycloalkenyl is optionally substituted with one substituent being fluoroor C₁₋₂alkyl (e.g. methyl); more preferably the R³ cycloalkenyl issubstituted with one fluoro substituent or is unsubstituted. For R³cycloalkenyl, the optional substituent(s) can be at the 1-, 2-, 3-, 4-or 5-position(s) of the cycloalkenyl ring.

Where R³ is the heterocyclic group of sub-formula (aa), (bb) or (cc),then Y is preferably O, S, SO₂, NH or N—C(O)methyl, more preferably O,NH or N—C(O)methyl, still more preferably O or N—C(O)methyl, mostpreferably O. (When Y is NH or N—C(O)methyl, then R¹⁰ is H orC(O)methyl).

Preferably, R¹⁰ is a hydrogen atom (H), methyl, ethyl, C(O)NH₂,C(O)methyl or C(O)—CF₃. Optionally, R¹⁰ can be a hydrogen atom (H),methyl, ethyl, C(O)methyl or C(O)—CF₃, more preferably H, C(O)methyl orC(O)—CF₃, still more preferably H or C(O)methyl.

Where R³ is the heterocyclic group of sub-formula (aa), (bb) or (cc),then it is preferable that R³ is the heterocyclic group of sub-formula(aa) or (bb), more preferably of sub-formula (bb).

In sub-formula (bb), n¹ is preferably 1. In sub-formula (cc), n² ispreferably 1. That is, six-membered rings are preferred in the R³heterocyclic group.

Suitably, in R³, the heterocyclic group of sub-formula (aa), (bb) or(cc) is unsubstituted (In this connection, where Y is NR¹⁰, R¹⁰ is notclassified as a substituent).

In the R³ heterocyclic group of sub-formula (aa), (bb) or (cc), the oneor two optional substituents preferably comprise (e.g. is orindependently are ((e.g. is or are)) OH; oxo (═O); C₁₋₂alkyl (e.g.methyl) or C₁₋₂fluoroalkyl (e.g. C₁fluoroalkyl such as —CH₂F or —CHF₂).More preferably, in the R³ heterocyclic group of sub-formula (aa), (bb)or (cc), the one or two optional substituents comprise (e.g. is orindependently are ((e.g. is or are)) OH and/or oxo; most preferably theone or two optional substituents comprise (e.g. is or are) oxo (═O). Inthe R³ heterocyclic group of sub-formula (aa), (bb) or (cc), any oxo(═O) substituents are preferably on a carbon atom bonded (adjacent) toX, and/or can be at the 2-, 3-, 4- or 5-position(s) of the R³heterocyclic ring. (In this connection, the 1-position of the R³heterocyclic ring is deemed to be the connection point to the —NH— informula (I)). Preferably, only C₁₋₂alkyl, C₁₋₂fluoroalkyl, fluoro or oxo(═O) substitution or no substitution is allowed at each of the 2- and6-positions of the R³ heterocyclic ring.

When R³ is the heterocyclic group of sub-formula (aa) and Y is NR¹⁰,then preferably R¹⁰ is not C(O)-Me. More preferably, when R³ is theheterocyclic group of sub-formula (aa) and Y is NR¹⁰, then R¹⁰ ispreferably not C(O)R, i.e. or e.g. R¹⁰ is preferably not C(O)NH₂,C(O)—C₁₋₂alkyl or C(O)—C₁fluoroalkyl. In one embodiment, Y is O, S, SO₂or NH when R³ is the heterocyclic-group of sub-formula (aa).

Optionally, according to one embodiment of the invention, NHR³ is not

More preferably, when R³ is the heterocyclic group of sub-formula (bb)and Y is NR¹⁰, and optionally when n¹ is 1, then preferably R¹⁰ is notmethyl. More preferably, when R³ is the heterocyclic group ofsub-formula (bb) and Y is NR¹⁰, and optionally when n¹ is 1, then R¹⁰ ispreferably not alkyl or substituted alkyl, i.e. or e.g. R¹⁰ ispreferably not C₁₋₄alkyl (e.g. methyl or ethyl), C₁₋₂fluoroalkyl orCH₂C(O)NH₂. In one embodiment, when R³ is the heterocyclic group ofsub-formula (bb), Y is preferably O, S, SO₂ or NR¹⁰, wherein R¹⁰ is H,C(O)NH₂, C(O)—C₁₋₂alkyl or C(O)—C₁fluoroalkyl, or more preferably Y is Hor C(O)Me. More preferably, for sub-formula (bb), Y is O or NR¹⁰.

Where R³ is a bicyclic group of sub-formula (dd) or (ee), preferably itis of sub-formula (ee). In sub-formula (ee), preferably Y¹, Y² and Y³are all CH₂.

Preferably, NHR³ is of sub-formula (a), (a1), (b), (c), (c1), (c2),(c3), (c4), (c5), (c6), (c7), (d), (e), (f), (g), (g1), (g2), (g3),(g4), (h), (i), (j), (k), (k1), (L), (m), (m1), (m2), (m3), (m4), (m5),(n), (o), (o1), (o2), (o3), (o4), (o5), (p), (p1), (p2), (p3), (p4),(p5), (p6), (p7), (p8) or (q):

In the sub-formulae (a) to (q) etc above, the —NH— connection point ofthe NHR³ group to the 4-position of the pyrazolopyridine of formula (I)is underlined.

Preferably, NHR³ is of sub-formula (c), (c1), (c2), (c3), (c4), (c5),(c6), (c7), (d), (e), (f), (g1), (g4), (h), (i), (j), (k), (k1), (L),(m), (m1), (m2), (m3), (m5), (n), (o), (o1), (o2), (o3), (o4), (o5),(p), (p2), (p3), (p5), (p6), (p7) or (q). More preferably, NHR³ is ofsub-formula (c), (c1), (c4), (c5), (h), (i), (j), (k), (m1), (m2), (n),(o), (o2), (o3), (p2), (p5), (p6) or (q). Still more preferably, NHR³ isof sub-formula (c), (h), (k), (n), (o) or (o2); for example (c), (h),(o) or (o2). Most preferably, R³ is tetrahydro-2H-pyran-4-yl; that isNHR³ is most preferably of sub-formula (h), as shown above.

According to one embodiment, NHR³ is of sub-formula (a), (b), (c), (d),(e), (f), (g), (g1), (g2), (g3), (h), (i), (j), k), (L), (m), (m1), (n),(o), (o1), (p) or (q). In this embodiment, preferably, NHR³ is ofsub-formula (c), (d), (e), (f), (g1), (h), (i), (j), (k), (m), (m1),(n), (o), (o1), (p), or (q); and more preferably in this embodiment,NHR³ is of sub-formula (c), (h), (i), (j), (k), (m1), (n), (o) or (q).Still more preferably in this embodiment, NHR³ is of sub-formula (c),(h), (k), (n) or (o). Most preferably, R³ is tetrahydro-2H-pyran-4-yl;that is NHR³ is most preferably of sub-formula (h), as shown above.

According to another embodiment, NHR³ is of sub-formula (a), (b), (c),(d), (e), (f), (g), (h), (i), (j) or (k). In this embodiment,preferably, NHR³ is of sub-formula (c), (d), (e), (f), (h), (i), (j) or(k); and more preferably in this embodiment, NHR³ is of sub-formula (c),(h), (i), (j) or k). Most preferably, R³ is tetrahydro-2H-pyran-4-yl;that is NHR³ is most preferably of sub-formula (h), as shown above.

When NHR³ is of sub-formula (n), then preferably it is acis-(3-hydroxycyclohex-1-yl)amino group, eg in any enantiomeric form ormixture of forms but preferably racemic.

Preferably, X is NR⁴R⁵.

Where R⁴ is C₁₋₆alkyl, then preferably it is C₁₋₄alkyl or C₁₋₂alkyl.Where R⁴ is C₁₋₃fluoroalkyl then preferably it is C₁₋₂fluoroalkyl.

Most preferably, R⁴ is a hydrogen atom (H).

Where R⁴ is C₂₋₆alkyl substituted by one substituent R¹, then preferablyR⁴ is C₂₋₄alkyl (e.g. C₂₋₃alkyl) substituted by one substituent R¹¹.More preferably, R⁴ is —(CH₂)_(n) ³—R¹¹ wherein n³ is 2, 3 or 4. Stillmore preferably, n³ is 2 and/or R⁴ is —(CH₂)_(n) ³—OH.

When R⁵ is C₂₋₆alkyl substituted by one or two independent substituentsR¹¹, it is preferable that R⁵ is C₂₋₄alkyl (e.g. C₂₋₃alkyl) substitutedby one or two independent substituents R¹¹. When R⁵ is C₂₋₆alkyl (e.g.C₂₋₄alkyl or C₂₋₃alkyl) substituted by one or two independentsubstituents R¹¹, it is preferable that R⁵ is C₂₋₆alkyl (e.g. C₂₋₄alkylor C₂₋₃alkyl) substituted by one substituent R¹¹. It is more preferablethat R⁵ is —(CH₂)_(n) ⁵—R¹¹ wherein n⁵ is 2, 3 or 4. Preferably n⁵ is 2or 3, more preferably 2.

Preferably, each substituent R¹¹, independently of any other R¹¹substituent present, is: hydroxy (OH); C₁₋₆alkoxy (e.g. C₁₋₄alkoxy suchas t-butyloxy, ethoxy or methoxy); phenyloxy; benzyloxy; —NR¹²R¹³;—NR¹⁵—C(O)R¹⁶; —NR¹⁵—C(O)—NH—R¹⁵; or —NR¹⁵—SO₂R¹⁶ (more preferablyC₁₋₆alkoxy, —NR¹⁵—C(O)—NH—R¹⁵, or —NR¹⁵—SO₂R¹⁶; most preferably—NR¹⁵—SO₂R¹⁶). In all cases, any R¹ substituent which is OH, alkoxy or—NR¹²R¹³ is not substituted at any carbon atom, of any R⁴ or R⁵substituted alkyl, which is bonded to the nitrogen of NR⁴R⁵.

Where R⁵ is C₁₋₈alkyl, then preferably it is C₁₋₅alkyl or C₁₋₃alkyl.Where R⁵ is C₁₋₈fluoroalkyl then preferably it is C₁₋₃fluoroalkyl orC₁₋₂fluoroalkyl. Where R⁵ is C₃₋₈cycloalkyl optionally substituted by aC₁₋₂alkyl group, then preferably the C₃₋₈cycloalkyl is not substitutedat the ring-carbon bonded to the nitrogen of NR⁴R⁵. Where R⁵ isoptionally substituted C₃₋₈cycloalkyl, then more preferably it isC₃₋₈cycloalkyl (i.e. unsubstituted).

When R⁵ is optionally substituted —(CH₂)_(n) ⁴—C₃₋₈cycloalkyl wherein n⁴is 1, 2 or 3, then n⁴ is preferably 1 or 2 or more preferably 1, and/orpreferably R⁵ is optionally substituted —(CH₂)_(n) ⁴—C₅₋₆cycloalkyl oroptionally substituted —(CH₂)_(n) ⁴—C₆cycloalkyl. When R⁵ is optionallysubstituted —(CH₂)_(n) ⁴—C₃₋₈cycloalkyl, preferably it is notsubstituted. Most preferably R⁵ is (cyclohexyl)methyl-, that is—CH₂-cyclohexyl.

When R¹⁹ is C₁₋₄alkyl, then preferably it is isobutyl, sec-butyl, orC₁₋₃alkyl such as methyl or isopropyl. When R¹⁹ is —(CH₂)_(n) ²⁰—OR²⁰,then preferably n²⁰ is 1 and/or preferably R²⁰ is a hydrogen atom (H).

When R⁵ is —(CH₂)_(n) ¹¹—C(O)R¹⁶; —(CH₂)_(n) ¹²—C(O)NR¹²R¹³;—CHR¹⁹—C(O)NR¹²R¹³; —(CH₂)_(n) ¹²—C(O)OR¹⁶; —CHR¹⁹—C(O)OR¹⁶; —(CH₂)_(n)¹²—SO₂—NR¹²R¹³; —(CH₂)_(n) ¹²—SO₂R¹⁶; or —(CH₂)_(n) ¹²—CN; then in oneembodiment of the invention R⁵ can be: —(CH₂)_(n) ¹¹—C(O)R¹⁶; —(CH₂)_(n)¹²—C(O)NR¹²R¹³; —(CH₂)_(n) ¹²—C(O)OR¹⁶; —(CH₂)_(n) ¹²—SO₂—NR¹²R¹³;—(CH₂)_(n) ¹²—SO₂R¹⁶; or —(CH₂)_(n) ¹²—CN.

When R⁵ is —(CH₂)_(n) ¹¹—C(O)R¹⁶; —(CH₂)¹¹²—C(O)NR¹²R¹³; —(CH₂)_(n)²—C(O)OR¹⁶; —(CH₂)_(n) ¹²—SO₂—NR¹²R¹³; —(CH₂)_(n) ¹²—SO₂R¹⁶; or—(CH₂)_(n) ¹¹²—CN; then R⁵ can for example be —(CH₂)_(n) ¹¹—C(O)R¹⁶;—(CH₂)_(n) ¹²—C(O)NR¹²R¹³; or —(CH₂)_(n) ¹²—CN; preferably —(CH₂)_(n)¹¹—C(O)R¹⁶.

Preferably, n¹¹ is 1, 2, 3 or 4; more preferably n¹¹ is 1 or 2.Advantageously, n¹² is 1 or 2.

When R⁵ is —(CH₂)_(n) ¹³—Het, it is preferable that n¹³ is 0, 1 or 2,more preferably 0 or 1.

Preferably, Het is a 5- or 6-membered saturated or partly-saturatedheterocyclic ring and/or preferably is a 4-, 5-, 6- or 7-memberedsaturated heterocyclic ring. Preferably, the heterocyclic ring Hetcontains one ring-hetero-atom selected from O, S and N.

Preferably, the carbon ring-atoms in Het are not substituted. Het ismost preferably one of:

When R⁵ is optionally substituted phenyl, then preferably it is phenyloptionally substituted with one or two of the substituents definedherein.

When R⁵ is optionally substituted phenyl, then preferably R⁵ is phenyloptionally substituted with, independently, one, two or three(preferably one or two; or one) of: a halogen atom (preferably fluoroand/or chloro); C₁₋₂alkyl; C₁₋₂fluoroalkyl (e.g. trifluoromethyl);C₁₋₂alkoxy (e.g. methoxy); trifluoromethoxy, C₁₋₂alkylsulphonyl(C₁₋₂alkyl-SO₂—); C₁₋₂alkyl-SO₂—NH—; R⁷R⁸N—SO₂—; R⁷R⁸N—CO—;—NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH; C₁₋₂alkoxymethyl; C₁₋₂alkyl-SO₂—CH₂—; cyano(CN); or phenyl optionally substituted by one of fluoro, C₁₋₂alkyl,C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy. More preferably R⁵ isphenyl optionally substituted with one or two (preferably one) of: ahalogen atom, C₁₋₂alkyl, trifluoromethyl, C₁₋₂alkoxy, trifluoromethoxy,R⁷R⁸N—SO₂—, R⁷R⁸N—CO—, or C₁₋₂alkyl-SO₂—CH₂—. When R⁵ is optionallysubstituted phenyl, then preferably one or all of the one or twooptional substituents are substituted at the meta-(3- and/or 5-) and/orpara-(4-) position(s) of the phenyl ring with respect to the phenylring-carbon bonded to the nitrogen of NR⁴R⁵.

Preferably, R⁷ and/or R⁸ are independently a hydrogen atom (H);C₁₋₂alkyl such as methyl; C₃₋₆cycloalkyl; or phenyl optionallysubstituted by one of: fluoro, chloro, C₁₋₂alkyl, C₁fluoroalkyl,C₁₋₂alkoxy or C fluoroalkoxy; or R⁷ and R⁸ together are —(CH₂)_(n) ⁶— or—(CH₂)_(n) ⁸—X⁷—(CH₂)_(n) ⁹— wherein X⁷ is NR¹⁴ or preferably O.

When R⁷ is cycloalkyl or optionally substituted phenyl, then preferablyR⁸ is neither cycloalkyl nor optionally substituted phenyl.

Most preferably, R⁷ and/or R⁸ independently are a hydrogen atom (H) orC₁₋₂alkyl. It is preferable that R⁷ is a hydrogen atom (H).

Preferably n⁶ is 4 or 5. Preferably n⁷ is 2, 3 or 4. Preferably, n⁸, n⁹and/or n¹⁰ is/are independently 2.

In general, it is preferable that R⁵ has the sub-formula (x) or (y) or(y1) or (z).

When R⁵ has the sub-formula (x) or (y) or (y1) or (z), then preferablyR⁵ has the sub-formula (x) or (y) or (y1) or has the sub-formula (x) or(y) or (z). More preferably R⁵ has the sub-formula (x) or (y), mostpreferably (x). In one embodiment, R⁵ has the sub-formula (z).

Preferably, n is 1 or 2. More preferably, n=1. Preferably, m=1.Preferably, r=1 or 2, more preferably 1.

In sub-formula (x), (y) and/or (y1), it is preferred that none, one ortwo of A, B, D, E and F are nitrogen; none, one, two or three of A, B,D, E and F are CR⁶; and the remaining of A, B, D, E and F are CH. Morepreferably, none, one or two of A, B, D, E and F are nitrogen; none, oneor two of A, B, D, E and F are CR⁶; and the remaining of A, B, D, E andF are CH.

In sub-formula (x), (y) and/or (y1), preferably, none or one of A, B, D,E and F are nitrogen, and/or preferably none, one or two of A, B, D, Eand F are CR⁶.

Preferably, sub-formula (x) is: benzyl; phenethyl (Ph-C₂H₄—); benzylsubstituted on the phenyl ring with one or two R⁶ substituents;phenethyl (Ph-C₂H₄—) substituted on the phenyl ring with one or two R⁶substituents; or one of the following:

, wherein R^(6a) is either R⁶ as defined herein or preferably) hydrogen.

Most preferably, sub-formula (x) is benzyl or pyridinylmethyl [e.g.pyridin-4-ylmethyl

pyridin-3-ylmethyl, or preferably pyridin-2-ylmethyl

Preferably, sub-formula Cy) is:

-   wherein R^(6a) is or independently are either R⁶ as defined herein    or preferably hydrogen. Preferably, sub-formula (y) is not    substituted by oxo (═O) at the carbon between the 6-membered    aromatic ring and the carbon bonded to the nitrogen of NR⁴R⁵.

Preferably, sub-formula (y1) is:

wherein R^(6a) is or independently are either R⁶ as defined herein orpreferably hydrogen.

Preferably, in sub-formula (z), none, one or two of J, L, M and Q arenitrogen.

In sub-formula (x), (y) and/or (z), preferably, each R⁶, independentlyof any other R⁶ present, is a fluorine, chlorine, bromine or iodineatom, methyl, ethyl, n-propyl, isopropyl, C₄alkyl, trifluoromethyl,—CH₂OH, methoxy, ethoxy, C₁fluoroalkoxy (e.g. trifluoromethoxy ordifluoromethoxy), OH, C₁₋₃alkylS(O)₂— (such as methylsulphonyl which isMeS(O)₂—), C₁₋₃alkylS(O)₂—NH— such as methyl-SO₂—NH—, Me₂N—S(O)₂—,H₂N—S(O)₂—, —CONH₂, —CONHMe, —CO₂H, cyano (CN), NMe₂, t-butoxymethyl, orC₁₋₃alkylS(O)₂—CH₂— such as methyl-SO₂—CH₂—. More preferably, each R⁶,independently of any other R⁶ present, is a fluorine, chlorine, bromineor iodine atom, methyl, ethyl, n-propyl, isopropyl, isobutyl,trifluoromethyl, —CH₂OH, methoxy, ethoxy, C₁fluoroalkoxy (e.g.trifluoromethoxy or difluoromethoxy), C₁₋₃alkylS(O)₂— such asmethylsulphonyl, C₁₋₃alkylS(O)₂—NH— such as methyl-SO₂—NH—, Me₂N—S(O)₂—,H₂N—S(O)₂—, —CONH₂, or C₁₋₃alkylS(O)₂—CH₂— such as methyl-SO₂—CH₂. Stillmore preferably, each R⁶, independently of any other R⁶ present, is afluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl,trifluoromethyl, —CH₂OH, methoxy, difluoromethoxy, methylsulphonyl,methyl-SO₂—NH— or methyl-SO₂—CH₂—.

The above preferred R⁶ substituents are also, independently, thepreferred phenyl optional and independent substituents for where R⁵ isoptionally substituted phenyl.

In sub-formula (x) and/or (y), preferably, one, two or three R⁶substituents are present in B, D and/or E; so that for example insub-formula (x), one, two or three R⁶ substituents are present in themeta-(3- and/or 5-) and/or para-(4-) positions with respect to the—(CH₂)_(n)— side-chain.

Preferably, R⁵ has the sub-formula (x), n is 1 and none of A, B, D, Eand F are nitrogen or nitrogen-oxide (N⁺—O⁻); and all of A, B, D, E andF are independently CH or CR⁶; that is R⁵ has the sub-formula (x) and isoptionally substituted benzyl. In this embodiment, preferably, a R⁶substituent is present at the 4-position with respect to the——(CH₂)_(n)— side-chain (that is D is CR⁶: i.e. a R⁶ substituent ispresent in D); and/or preferably a R⁶ substituent is present at the 3-and/or 5-position with respect to the —(CH₂)_(n)— side-chain (that is Band/or E is CR⁶: i.e. one or two R⁶ substituents are present in B and/orE). For monosubstitution, i.e. where one of A, B, D, E and F is CR⁶,then the one R⁶ substituent is preferably present at the 4-position withrespect to the ——(CH₂)_(n)— side-chain (i.e. D is CR⁶). Where there isdisubstitution, that is where two of A, B, D, E and F are independentlyCR⁶, then 3,4-disubstitution (B+D or D+E are independently CR⁶),2,4-disubstitution (A+D or D+F are independently CR⁶) or2,3-disubstitution (A+B or E+F are independently CR⁶) is preferred.

In sub-formula (x) and/or (y), any optional R⁶ substituent canoptionally be present only in B, D and/or E, so that in sub-formula (x)any optional R⁶ substituent is present only in the meta-(3- and/or 5-)and/or para-(4-) positions with respect to the ——(CH₂)_(n)— side-chain.Alternatively, in sub-formula (x), any optional R⁶ substituent can bepresent in the ortho-(2- and/or 6-) position with respect to the—(CH₂)_(n)— side-chain, either alone or in combination with one or moreother optional R⁶ substituents.

Overall for R⁵, it is preferable that R⁵ is a hydrogen atom (H);C₁₋₆alkyl (e.g. C_(1-2 or 3)alkyl or C₃₋₆alkyl); C₁₋₄fluoroalkyl,C₃₋₆cycloalkyl (e.g. C₅₋₆cycloalkyl), (C₅₋₆cycloalkyl)methyl-, phenyloptionally substituted with one or two of: a fluorine or chlorine atom,methyl, trifluoromethyl, methoxy or trifluoromethoxy; or R⁵ has thesub-formula (x), (y) or (z), for example as described above.

Still more preferably, R⁵ is a hydrogen atom (H), methyl, ethyl,n-propyl, iso-propyl, 2-ethylbutan-1-yl, cyclopentyl, cyclohexyl,(cyclohexyl)methyl-, optionally substituted phenyl e.g. fluorophenyle.g. 4-fluorophenyl, optionally substituted benzyl, or optionallysubstituted pyridinylmethyl, or R⁵ has the sub-formula (z).

Optionally, R⁵ can be benzyl, pyridinylmethyl (e.g. pyridin-4-ylmethyl,pyridin-3-ylmethyl, or preferably pyridin-2-ylmethyl), or4-fluorophenyl.

In one preferable embodiment, R⁵ has the sub-formula (x) and is: benzyl,(monoalkyl-phenyl)methyl, [mono(fluoroalkyl)-phenyl]methyl,(monohalo-phenyl)methyl, (monoalkoxy-phenyl)methyl,[mono(fluoroalkoxy)-phenyl]methyl,[mono(N,N-dimethylamino)-phenyl]methyl,[mono(methyl-SO₂—NH—)-phenyl]methyl, [mono(methyl-SO₂—)-phenyl]methyl,(dialkyl-phenyl)methyl, (monoalkyl-monohalo-phenyl)methyl,[mono(fluoroalkyl)-monohalo-phenyl]methyl, (dihalo-phenyl)methyl,(dihalo-monoalkyl-phenyl)methyl,[dihalo-mono(hydroxymethyl)-phenyl]methyl, or (dialkoxy-phenyl)methylsuch as (3,4-dimethoxy-phenyl)methyl. The substituents can preferably befurther defined, as defined in preferable embodiments herein.

In one preferable embodiment, R⁵ is of sub-formula (x) and is:(monoalkyl-phenyl)methyl, [mono(fluoroalkyl)-phenyl]methyl,(monohalo-phenyl)methyl, (monoalkoxy-phenyl)methyl,[mono(fluoroalkoxy)-phenyl]methyl,[mono(N,N-dimethylamino)-phenyl]methyl, (dialkyl-phenyl)methyl,(monoalkyl-monohalo-phenyl)methyl, (dihalo-phenyl)methyl or(dihalo-monoalkyl-phenyl)methyl or[dihalo-mono(hydroxymethyl)-phenyl]methyl. More preferably, in thisembodiment, R⁵ is: -(monoC₁₋₃alkyl-phenyl)methyl such as(4-C₁₋₃alkyl-phenyl)methyl; -(monoC₁fluoroalkyl-phenyl)methyl such as(4-C₁fluoroalkyl-phenyl)methyl; -(monoC₁₋₂alkoxy-phenyl)methyl such as(4-C₁₋₂alkoxy-phenyl)methyl; -[mono(C₁fluoroalkoxy)-phenyl]methyl suchas (4-C₁fluoroalkoxy-phenyl)methyl; -(diC₁₋₂alkyl-phenyl)methyl or(dimethyl-phenyl)methyl such as (3,4-dimethyl-phenyl)methyl,(2,4-dimethyl-phenyl)methyl, (3,5-dimethyl-phenyl)methyl,(2,3-dimethyl-phenyl)methyl or (2,5-dimethyl-phenyl)methyl; morepreferably (3,4-dimethyl-phenyl)methyl or (2,4-dimethyl-phenyl)methyl;-(monoC₁₋₂alkyl-monohalo-phenyl)methyl or(monoC₁₋₂alkyl-monochloro-phenyl)methyl such as(4-methyl-3-chloro-phenyl)methyl, (3-methyl-4-chloro-phenyl)methyl,(2-methyl-4-chloro-phenyl)methyl; -(dihalo-phenyl)methyl such as(2-chloro-4-fluorophenyl)methyl or (2,4-difluoro-phenyl)methyl or(4-bromo-2-fluorophenyl)methyl or preferably(4-chloro-2-fluorophenyl)methyl; for example (dichloro-phenyl)methylsuch as (3,4-dichloro-phenyl)methyl or (2,4-dichloro-phenyl)methyl or(2,6-dichloro-phenyl)methyl or preferably (2,3-dichloro-phenyl)methyl;-(dihalo-monoC₁₋₂alkyl-phenyl)methyl e.g.(2,4-dichloro-6-methyl-phenyl)methyl; or-[dihalo-mono(hydroxymethyl)-phenyl]methyl such as[2,3-dichloro-6-(hydroxymethyl)-phenyl]methyl.

In an alternative preferable embodiment, R⁵ has the sub-formula (z), andone or preferably none of J, L, M or Q is CR⁶, and/or R⁹ is a hydrogenatom (H) or methyl. Preferably r is 1. Preferably, for (z), R⁶ isindependently OH (including any keto tautomer thereof), or morepreferably C₁₋₂alkyl (e.g. methyl) or C₁fluoroalkyl.

Preferably NR⁴R⁵ is not NH₂. R⁵ is preferably not a hydrogen atom (H).

When R⁴ and R⁵ taken together are optionally substituted —(CH₂)_(p) ¹—or optionally substituted —C(O)—(CH₂)_(p) ²— or —(CH₂)_(p)³—X⁵—(CH₂)_(p) ⁴— or —C(O)—X⁵—(CH₂)_(p) ⁵— or a partially unsaturatedderivative of any of the foregoing, preferably R⁴ and R⁵ taken togetherare optionally substituted —(CH₂)_(p) ¹— or optionally substituted—C(O)—(CH₂)_(p) ²— or —(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴— or —C(O)—X⁵—(CH₂)_(p)⁵— (i.e. not a partially unsaturated derivative of any of these).

When R⁴ and R⁵ taken together are ——(CH₂)_(p) ¹— optionally substitutedby R¹⁸, or —C(O)—(CH₂)_(p) ²— optionally substituted by R¹⁸, or—(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴—, NR⁴R⁵ can for example be

optionally substituted by R¹⁸, or

optionally substituted by R¹⁸, or

optionally substituted by R¹⁸, or

(i.e. R⁴ and R⁵ taken together are —(CH₂)₂—N(R¹⁷)—(CH₂)₂—), or

(i.e. R⁴ and R⁵ taken together are —(CH₂)₂—O—(CH₂)₂—).

Preferably, R¹⁷ is a hydrogen atom (H); C₁₋₄alkyl (e.g. C₁₋₂alkyl);C₃₋₆cycloalkyl; —(CH₂)_(p) ⁶—C(O)R¹⁶, or the optionally substitutedphenyl or benzyl. More preferably, R¹⁷ is H; C₁₋₂alkyl; —(CH₂)_(p)⁶—C(O)R¹⁶ or the optionally substituted phenyl.

When R⁴ and R⁵ taken together are —(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²—,the NR⁴R⁵ heterocycle is preferably not substituted by R¹⁸.

When R⁴ and R⁵ taken together are —(CH₂)_(p) ¹— or —C(O)—(CH₂)*²—, andif the NR⁴R⁵ heterocycle is substituted by R¹⁸, then optionally R¹⁸ isnot substituted at a ring-carbon bonded to the NR⁴R⁵ ring-nitrogen.

When R⁴ and R⁵ taken together are ——(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²—or —(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴— or —C(O)—X⁵—(CH₂)_(p) ⁵— or a partiallyunsaturated derivative of any of these, and wherein the NR⁴R⁵heterocycle is fused to a phenyl ring optionally substituted on thephenyl by one or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl,C₁₋₂alkoxy or C₁fluoroalkoxy; then in one embodiment of the inventionNR⁴R⁵ is

wherein the phenyl is optionally substituted by one or two of: a halogenatom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy.

In one embodiment of the invention, NR⁷R⁸ and/or NR¹²R¹³ can for exampleindependently be

(i.e. R¹² and R¹³ together or R⁷ and R⁸ together are—(CH₂)₂—N(R¹⁴)—(CH₂)₂—), or (i.e. R¹² and R¹³ together or R⁷ and R⁸together are —(CH₂)₂—O—(CH₂)₂—), or NMe₂.

Preferably, R¹⁵ is a hydrogen atom (H) or C₁₋₄alkyl (e.g. tBu orC₁₋₂alkyl e.g. methyl); more preferably, R¹⁵ is a hydrogen atom (H).

Preferably, however, R⁴ and R⁵ are not taken together, i.e. are nottaken together to form the NR⁴R⁵ ring systems described herein.

(Similar preferances apply for R^(5a) as for R⁵, except that R^(5a)cannot be a hydrogen atom. Most preferably, R^(5a) is ethyl.)

In an especially preferable embodiment, NR⁴R⁵ is the NR⁴R⁵ group asdefined in any one of: Examples 21-98, 100-182, 187-188, 191-200,201-203, 210-353, 355-651, 653-658, 660-664 and 665-686.

It is particularly preferred that the compound of formula (I) or thesalt thereof is:

-   Ethyl    4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    1-ethyl-4-tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    4-[(1-acetylpiperidin-4-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    4-(cyclopentylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate    (not this compound per se, and for the use or method of treatment    preferably not this compound),-   Ethyl    1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    1-ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    1-ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    1-ethyl-4-(tetrahydrothien-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    4-(cyclopropylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   N-Benzyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Cyclopentyl-4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-Cyclohexylamino)-N-cyclopentyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Cyclopentyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-[(1-Acetylpiperidin-4-yl)amino]-N-cyclopentyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Cyclopentyl-1-ethyl-5-(pyrrolidin-1-ylcarbonyl)-1H-pyrazolo[3,4-b]pyridin-4-amine,-   N-Cyclohexyl-1-ethyl-5-(pyrrolidin-1-ylcarbonyl)-1H-pyrazolo[3,4-b]pyridin-4-amine,-   1-Ethyl-5-(pyrrolidin-1-ylcarbonyl)-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine,-   4-(Cyclopentylamino)-1-ethyl-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclohexylamino)-1-ethyl-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(pyridin-4-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-4-tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-4-cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-[(1-Acetylpiperidin-4-yl)amino]-N-benzyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclopentylamino)-1-ethyl-N-(2-ethylbutyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclohexylamino)-1-ethyl-N-(2-ethylbutyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-2-ethylbutyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(2-ethylbutyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-[(1-Acetylpiperidin-4-yl)amino]-ethyl-N-(2-ethylbutyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-Cyclopentylamino)-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclohexylamino)-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-4-fluorophenyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-[(1-Acetylpiperidin-4-yl)amino]-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-Cyclopentylamino)-1-ethyl-N-n-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclohexylamino)-1-ethyl-N-n-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-[(1-Acetylpiperidin-4-yl)amino]-1-ethyl-N-n-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-[(1-Acetylpiperidin-4-yl)amino]-1-ethyl-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-4-cyclopentylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-4-(cyclohexylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclopentylamino)-N-(2-ethylbutyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-Cyclohexylamino)-N-(2-ethylbutyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(2-Ethylbutyl)-1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-Cyclopentylamino)-N-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclohexylamino)-N-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(4-Fluorophenyl)-1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclopentylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclohexylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-[(1-Acetylpiperidin-4-yl)amino]-N-benzyl-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N,N-dimethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-isopropyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-1-ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-1-ethyl-4-(tetrahydrothien-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-4-(cyclopropylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-1-ethyl-4-tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(4-fluorophenyl)-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(4-fluorophenyl)-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(4-fluorophenyl)-4-(tetrahydrothien-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclopropylamino)-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-[(1,1-Dioxidotetrahydrothien-3-yl)amino]-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,    or-   4-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;-   or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.

The structures of these specific compounds are given in Examples 1-98hereinafter.

Alternatively, it is particularly preferred that the compound of formula(I) or the salt thereof is:

-   1-Ethyl-N-[4-(methylsulfonyl)benzyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[3-(methylsulfonyl)benzyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-5-{[5-methoxy-6-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine,-   N-[(5-Chloropyridin-2-yl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(4-Chlorobenzyl)-1-ethyl-N-isopropyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(3-Chlorobenzyl)-1-ethyl-N-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(2-tert-Butoxyethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(1,3-thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(pyrimidin-4-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[(2-methyl-1,3-thiazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-[3-(tert-Butoxymethyl)benzyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-{2-[methyl(methylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(pyrazin-2-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-5-{[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]carbonyl}-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine,-   N-(2-Chloro-6-fluorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-[3-(Aminocarbonyl)benzyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-{4-[(methylamino)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[2-(1-methyl-1H-imidazol-4-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-{2-[(Anilinocarbonyl)amino]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(1H-tetraazol-5-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   tert-Butyl    4-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)piperidine-1-carboxylate,-   1-Ethyl-N-{3-[(methylsulfonyl)amino]propyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-[2-(Dimethylamino)benzyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[(1-ethylpyrrolidin-2-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(tetrahydrofuran-2-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-ethyl-N-tetrahydro-2H-pyran-4-yl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-{4-[(Dimethylamino)sulfonyl]benzyl)}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-{3-[(methylsulfonyl)amino]benzyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(4-methoxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[3-(2-oxopyrrolidin-1-yl)propyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(pyridin-3-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(1-methylpiperidin-4-yl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(1-ethylpropyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(2-piperidin-1-ylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(3-morpholin-4-ylpropyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(3-Ethoxypropyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(Cyclohexylmethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-[3-(Dimethylamino)propyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-neopentyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-ethyl-N-(4-methoxybenzyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-{2-[(phenylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-[2-(Acetylamino)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-{2-[(methylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-{2-[(2-methoxyphenyl)(methyl)amino]ethyl}4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(2-oxo-2-phenylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(2,5-Difluorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N,1-Diethyl-N-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(2-amino-2-oxoethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-(3-methoxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(3,4-Difluorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   Ethyl    3-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)propanoate,-   N-(1-Benzylpiperidin-4-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Butyl-4-{[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}piperazine-1-carboxamide,-   1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(1,3,4-thiadiazol-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(2,3-Dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[2-(2-oxoimidazolidin-1-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(3,4-Dimethoxybenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(3-Chlorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-5-[(4-methylpiperazin-1-yl)carbonyl]-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine,-   1-Ethyl-N-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-S-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine,-   1-Ethyl-N-{4-[(methylsulfonyl)methyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-[3-(dimethylamino)-3-oxopropyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[(1-methyl-1H-imidazol-5-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-{4-[(methylamino)sulfonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(2-Cyanoethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-methyl-N-[(1-methyl-1H-imidazol-2-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(2-thien-2-ylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-[2-(4-Chlorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   1-Ethyl-N-[2-(2-methoxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   Ethyl    4-(cyclohexylamino)-1-(3-ethoxy-3-oxopropyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    1-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   N-[4-(Methylsulfonyl)benzyl]-1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-(4-Fluorophenyl)-1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   Ethyl    1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   Ethyl    4-(cyclohexylamino)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,-   4-(Cyclohexylamino)-1-ethyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-4-(cyclohexylamino)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclohexylamino)-1-ethyl-N-(4-fluorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclohexylamino)-1-ethyl-6-methyl-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   4-(Cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-1-ethyl-4-[(2-oxoazepan-3-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-1-ethyl-4-[(3-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-1-ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,-   N-Benzyl-1-ethyl-4-[(3-hydroxycyclopentyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,    or-   N-Benzyl-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;-   or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.

The structures of these specific compounds are given in Examples 100-201hereinafter.

Alternatively, the compound of formula (I) or the salt thereof can be:

-   1-Ethyl-N-(2-hydroxy-1-methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,    or-   Methyl    (2S)-2-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)-3-hydroxypropanoate;-   or a salt thereof, e.g. a pharmaceutically acceptable salt thereof.    (See for example Examples 202-203).

Alternatively, it is particularly preferred that the compound of formula(I) or the salt thereof is one of Examples 204 to 664 or one of Examples665 to 686, as a compound or a salt thereof, e.g. a pharmaceuticallyacceptable salt thereof. The structures of these specific compounds aregiven in Examples 204 to 664 and Examples 665 to 686 hereinafter, andtheir names are given in the Examples section.

In one embodiment, is still further preferred that the compound offormula (I) or the salt thereof is a compound of Example 260, 261, 263,266, 431, 493, 494, 518, 528, 584, 626, 643, 653, 679, 680, 681, 682,683, 684, 685 or 686 (more preferably Example 260, 518, 653, 679, 680,681 or 684), as defined by the structures and/or names described herein,or a salt thereof, e.g. a pharmaceutically acceptable salt thereof. Thestructures and names of these Examples are described in the Examplessection. These Examples are thought to be suitable for inhaledadministration.

In another embodiment, is still further preferred that the compound offormula (I) or the salt thereof is a compound of Example 21, 22, 83,100, 109, 167, 172, 178 or 600, as defined by the structures and/ornames described herein, or a salt thereof, e.g. a pharmaceuticallyacceptable salt thereof. The structures and names of these Examples aredescribed in the Examples section. These Examples are thought to besuitable for oral administration.

A second aspect of the present invention provides a compound of formula(IA) or a salt thereof (in particular, a pharmaceutically acceptablesalt thereof):

wherein:

-   X is NR⁴R⁵ or OR^(5a), in which:-   R⁴ is hydrogen, C₁₋₂alkyl or C₁₋₂fluoroalkyl, and-   R⁵ is hydrogen, C₁₋₈alkyl, C₁₋₈ fluoroalkyl, or C₃₋₈cycloalkyl,    phenyl optionally substituted with one or two of: a halogen atom,    C₁₋₂alkyl, trifluoromethyl, C₁₋₂alkoxy or trifluoromethoxy; or R⁵    has the sub-formula (x), (y) or (z):    -   wherein in sub-formula (x) and (z), n 1 or 2; and in sub-formula        (y), m=1 or 2;    -   wherein in sub-formula (x) and (y), none, one or two of A, B, D,        E and F are nitrogen; and the remaining of A, B, D, E and F are        CH or CR⁶ where R⁶ is a halogen atom, C₁₋₄alkyl,        C₁₋₄fluoroalkyl, C₁₋₂alkoxy, C₁₋₂fluoroalkoxy,        C₁₋₂alkylsulphonyl (C₁₋₂alkyl-SO₂—), C₁₋₂alkyl-SO₂—NH—,        R⁷R⁸N—SO₂—, R⁷R⁸N—CO—, R⁷R⁸N, OH, C₁₋₄alkoxymethyl, or        C₁₋₂alkyl-SO₂—CH₂—, wherein R⁷ and R⁸ are independently hydrogen        or C₁₋₂alkyl;    -   wherein in sub-formula (z), G is O or S or NR⁹ wherein R⁹ is        C₁₋₄alkyl or C₁₋₄fluoroalkyl; none, one or two of J, L, M and Q        are nitrogen; and the remaining of J, L, M and Q are CH or CR⁶        where R⁶ is as defined herein;-   or R⁴ and R⁵ taken together are ——(CH₂)_(p) where p=3, 4 or 5    (preferably p=4);-   R^(5a) is C₁₋₈alkyl; C₁₋₈ fluoroalkyl; C₃₋₈cycloalkyl; phenyl    optionally substituted with one or two of: a halogen atom,    C₁₋₂alkyl, trifluoromethyl, C₁₋₂alkoxy or trifluoromethoxy; or    R^(5a) has the sub-formula (x), (y) or (z) as defined herein;-   R³ is C₃₋₈cycloalkyl or a heterocyclic group being    in which Y is O, S, SO₂, or NR¹⁰; where R¹⁰ is hydrogen, C₁₋₄alkyl,    C₁₋₂fluoroalkyl, C(O)—C₁₋₂alkyl, or C(O)—CF₃;-   and wherein in R³ the C₃₋₈cycloalkyl or heterocyclic group is    optionally substituted with one or two substituents being OH,    C₁₋₂alkoxy, trimethoxy, or C₁₋₂alkyl group; and-   wherein any OH, alkoxy or trimethoxy substituent is not substituted    at the ring carbon attached to the —NH— group of formula (IA) and is    not substituted at either ring carbon bonded to the Y group of the    heterocyclic group; and-   R¹═C₁₋₄alkyl or C₁₋₂fluoroalkyl.

In formula (IA), preferably, when R³ is the heterocyclic group being

and Y is NR¹⁰, then:

-   either (a) R¹⁰ is hydrogen, C(O)—C₁₋₂alkyl, or C(O)—CF₃;-   or (b) R¹⁰ is methyl and the compound is:    1-ethyl-N-(2-ethylbutyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide    or    1-ethyl-N-(4-fluorophenyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide.

In formula (IA), preferably, where X is OR^(5a), the compound is otherthan the compound wherein R¹ is methyl, X is OEt, and R³ is cyclopentyl.

In formula (IA), in sub-formula (x) and/or (y), it is preferred thatnone, one or two of A, B, D, E and F are nitrogen; none, one, two orthree of A, B, D, E and F are CR⁶; and the remaining of A, B, D, E and Fare CH. More preferably, none, one or two of A, B, D, E and F arenitrogen; none or one or two of A, B, D, E and F are CR⁶; and theremaining of A, B, D, E and F are CH. In formula (IA), in sub-formula(x) and/or (y), preferably, none or one of A, B, D, E and F arenitrogen.

In formula (IA), preferably, sub-formula (x) is: benzyl; phenethyl(Ph-C₂H₄—); benzyl or phenethyl being substituted on the phenyl ringwith a single R⁶ substituent, or one of the following:

wherein R^(6a) is either R⁶ as defined herein or (preferably) hydrogen.

In formula (IA), preferably, sub-formula (y) is:

wherein R^(6a) is either R⁶ as defined herein or preferably hydrogen.

Examples 1-99 are examples of compounds or salts of the second aspect ofthe invention (Formula (IA)).

A third aspect of the present invention provides a compound of formula(IB) or a salt thereof (in particular, a pharmaceutically acceptablesalt thereof):

wherein:

-   R¹ is C₁₋₄alkyl, C₁₋₃fluoroalkyl, —CH₂CH₂OH or —CH₂CH₂CO₂C₁₋₂alkyl;-   R² is a hydrogen atom (H), methyl or C₁fluoroalkyl;-   R³ is optionally substituted C₃₋₈cycloalkyl or an optionally    substituted heterocyclic group of sub-formula (aa), (bb) or (cc);-   in which n¹ and n² independently are 1 or 2; and in which Y is O, S,    SO₂, or NR¹⁰; where R¹⁰ is a hydrogen atom (H), C₁₋₄alkyl (e.g.    methyl or ethyl), C₁₋₂fluoroalkyl, CH₂C(O)NH₂, C(O)NH₂,    C(O)—C₁₋₂alkyl, or C(O)—C₁fluoroalkyl;-   and wherein in R³ the C₃₋₈cycloalkyl or the heterocyclic group of    sub-formula (aa), (bb) or (cc) is optionally substituted with one or    two substituents being oxo (═O), OH, C₁₋₂alkoxy, C₁₋₂fluoroalkoxy    (e.g. trifluoromethoxy), or C₁₋₂alkyl; and wherein any OH, alkoxy or    fluoroalkoxy substituent is not substituted at the R³ ring carbon    attached (bonded) to the —NH— group of formula (IB) and is not    substituted at either R³ ring carbon bonded to the Y group of the    heterocyclic group (aa), (bb) or (cc); and X is NR⁴R⁵ or OR^(5a), in    which:-   R⁴ is a hydrogen atom (H); C₁₋₆alkyl; C₁₋₃fluoroalkyl; or C₂₋₆alkyl    substituted by one substituent R¹¹; and-   R⁵ is a hydrogen atom (H); C₁₋₈alkyl; C₁₋₈ fluoroalkyl;    C₃₋₈cycloalkyl optionally substituted by a C₁₋₂alkyl group; or    —(CH₂)_(n) ⁴—C₃₋₈cycloalkyl optionally substituted, in the    —(CH₂)_(n) ⁴— moiety or in the C₃₋₈cycloalkyl moiety, by a C₁₋₂alkyl    group, wherein n⁴ is 1, 2 or 3;-   or R⁵ is C₂₋₆alkyl substituted by one or two independent    substituents R¹¹;-   wherein each substituent R¹¹, independently of any other R¹¹    substituent present, is: hydroxy (OH); C₁₋₆alkoxy; phenyloxy;    benzyloxy; —NR¹²R¹³; —NR¹⁵—C(O)R¹⁶; —NR¹⁵—C(O)—O—R¹⁶;    —NR¹⁵—C(O)—NH—R¹⁵; or —NR¹⁵—SO₂R¹⁶; and wherein any R¹¹ substituent    which is OH, alkoxy or —NR¹²R¹³ is not substituted at any carbon    atom, of any R⁴ or R⁵ substituted alkyl, which is bonded to the    nitrogen of NR⁴R⁵;-   or R⁵ is —(CH₂)_(n) ¹¹—C(O)R¹⁶; —(CH₂)_(n) ¹¹—C(O)NR¹²R¹³;    —CHR¹⁹—C(O)NR¹²R¹³; —(CH₂)_(n) ¹²—C(O)OR¹⁶; —CHR¹⁹—C(O)OR¹⁶;    —(CH₂)_(n) ¹²—SO₂—NR¹²R¹³; —(CH₂)_(n) ¹²—SO₂R¹⁶; or —(CH₂)_(n)    ¹¹²—CN; wherein nil is 0, 1, 2, 3 or 4 and n¹² is 1, 2, 3 or 4;-   or R⁵ is —(CH₂)_(n) ¹³—Het wherein n¹³ is 0, 1, 2, 3 or 4 and Het is    a 4-, 5-, 6- or 7-membered saturated or partly-saturated    heterocyclic ring containing one or two ring-hetero-atoms    independently selected from O, S, and N; wherein any    ring-hetero-atoms present are not bound to the —(CH₂)_(n) ¹³— moiety    when n¹³ is 1 and are not bound to the nitrogen of NR⁴R⁵ when n¹³ is    0; wherein any ring-nitrogens which are present and which are not    unsaturated (i.e. which do not partake in a double bond) are present    as NR¹⁷ where R¹⁷ is as defined herein; and wherein one or two of    the carbon ring-atoms independently are optionally substituted by    C₁₋₂alkyl;-   or R⁵ is phenyl optionally substituted with one or two of: a halogen    atom; C₁₋₄alkyl (e.g. C₁₋₂alkyl); C₁₋₂fluoroalkyl (e.g.    trifluoromethyl); C₁₋₄alkoxy (e.g. C₁₋₂alkoxy); C₁₋₂fluoroalkoxy    (e.g. trifluoromethoxy); C₁₋₂alkylsulphonyl(C₁₋₂alkyl-SO₂—);    C₁₋₂alkyl-SO₂—NH—; R⁷R⁸N—SO₂—; R⁷R⁸N—CO—; —NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH;    C₁₋₄alkoxymethyl; C₁₋₄alkoxyethyl; C₁₋₂alkyl-SO₂—CH₂—; cyano (CN);    or phenyl optionally substituted by one or two of fluoro, chloro,    C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy;    -   wherein R⁷ and R⁸ are independently a hydrogen atom (H);        C₁₋₄alkyl (e.g. C₁₋₂alkyl such as methyl); C₃₋₆cycloalkyl; or        phenyl optionally substituted by one or two of: fluoro, chloro,        C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; or R⁷        and R⁸ together are —(CH₂)_(n) ⁶— or —C(O)—(CH₂)_(n) ⁷— or        —C(O)—(CH₂)_(n) ⁷—C(O)— or —(CH₂)_(n) ⁸—X⁷—(CH₂)_(n) ⁹— or        —C(O)—X⁷—(CH₂)_(n) ¹⁰— in which: n⁶ is 3, 4, 5 or 6, n⁷ is 2, 3,        4, or 5 (preferably n⁷ is 2, 3 or 4), n⁸ and n⁹ and n¹        independently are 2 or 3, and X⁷ is O or NR¹⁴ wherein R¹⁴ is H        or C₁₋₂alkyl;-   or R⁵ has the sub-formula (x), (y) or (z):-   wherein in sub-formula (x), n=1 or 2; in sub-formula (y), m=1 or 2;    and in sub-formula (z), r=0, 1 or 2;-   wherein in sub-formula (x) and (y), none, one or two of A, B, D, E    and F are nitrogen; and the remaining of A, B, D, E and F are    independently CH or CR⁶;-   where R⁶ is a halogen atom; C₁₋₄alkyl (e.g. C₁₋₂alkyl);    C₁₋₄fluoroalkyl (e.g. C₁₋₂fluoroalkyl); C₁₋₄alkoxy (e.g.    C₁₋₂alkoxy); C₁₋₂fluoroalkoxy; C₁₋₂alkylsulphonyl (C₁₋₂alkyl-SO₂—);    C₁₋₂alkyl-SO₂—NH—; R⁷R⁸N—SO₂—; R⁷R⁸N—CO—; —NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH;    C₁₋₄alkoxymethyl; C₁₋₄alkoxyethyl; C₁₋₂alkyl-SO₂—CH₂—; cyano (CN);    or phenyl optionally substituted by one or two of fluoro, chloro,    C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; wherein R⁷    and R⁸ are as herein defined;-   wherein in sub-formula (z), G is O or S or NR⁹ wherein R⁹ is a    hydrogen atom (H), C₁₋₄alkyl or C₁₋₄fluoroalkyl; none, one, two or    three of J, L, M and Q are nitrogen; and the remaining of J, L, M    and Q are independently CH or CR⁶ where R⁶ is as defined herein;-   or R⁴ and R⁵ taken together are ——(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²—    or —(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴— or —C(O)—X⁵—(CH₂)_(p) ⁵—, in which:    p¹=3, 4, 5 or 6 (preferably p=4 or 5), p² is 2, 3, 4, or 5    (preferably p² is 2, 3 or 4), and p³ and p⁴ and p⁵ independently are    2 or 3 (independently preferably 2) and X⁵ is O or NR¹⁷;    -   wherein R¹⁷ is a hydrogen atom ([); C₁₋₄alkyl (e.g. C₁₋₂alkyl);        C₁₋₂fluoroalkyl; C₃₋₆cycloalkyl; —(CH₂)_(p) ⁶—C(O)R¹⁶ wherein p⁶        is 0, 1, 2 or 3 (preferably p⁶ is 0); —(CH₂)_(p) ⁶—C(O)NR¹²R¹³;        —(CH₂)_(p) ⁶—C(O)OR¹⁶; —SO₂R¹⁶; or phenyl or benzyl wherein the        phenyl or benzyl is optionally substituted at an aromatic carbon        atom by one or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl,        C₁₋₂alkoxy or C₁fluoroalkoxy;    -   and wherein, when R⁴ and R⁵ taken together are ——(CH₂)_(p) ¹— or        —C(O)—(CH₂)_(p) ²—, the NR⁴R⁵ heterocycle is optionally        substituted by one R¹⁸ substituent wherein R¹⁸ is: C₁₋₄alkyl        (e.g. C₁₋₂alkyl); C₁₋₂fluoroalkyl; C₃₋₆cycloalkyl; C₁₋₂alkoxy        (not substituted at a ring-carbon bonded to the NR⁴R⁵        ring-nitrogen); C₁fluoroalkoxy (not substituted at a ring-carbon        bonded to the NR⁴R⁵ ring-nitrogen); OH (not substituted at a        ring-carbon bonded to the NR⁴R⁵ ring-nitrogen); —(CH₂)_(p)        ⁷—C(O)R¹⁶ wherein p⁷ is 0, 1, 2 or 3 (preferably p⁷ is 0 or 1);        —(CH₂)_(p) ⁷—C(O)OR¹⁶; —(CH₂)_(p) ⁷—OC(O)R¹⁶; —(CH₂)_(p)        ⁷—C(O)NR¹²R¹³; —(CH₂)_(p) ⁷—NR¹⁵C(O)R¹⁶; —(CH₂)_(p)        ⁷—NR¹⁵C(O)NR¹²R¹³; —(CH₂)_(p) ⁷—NR¹⁵C(O)OR¹⁶; —(CH₂)*⁷—SO₂R¹⁶;        —(CH₂)_(p) ⁷—SO₂ NR¹²R¹³; —(CH₂)_(p) ⁷—NR¹⁵SO₂R¹⁶; —(CH₂)_(p)        ⁷—OH; —(CH₂)_(p) ⁷—OR¹⁶; or phenyl optionally substituted by one        or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy        or C₁fluoroalkoxy;-   or R⁴ and R⁵ taken together are —(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²—    or —(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴— or —C(O)—X⁵—(CH₂)_(p) ⁵— as defined    herein, and wherein the NR⁴R⁵ heterocycle is fused to a phenyl ring    optionally substituted on the phenyl by one or two of: a halogen    atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; and-   R^(5a) is C₁₋₈alkyl; C₁₋₈ fluoroalkyl; C₃₋₈cycloalkyl; phenyl    optionally substituted with one or two of: a halogen atom,    C₁₋₂alkyl, trifluoromethyl, C₁₋₂alkoxy or trifluoromethoxy; or    R^(5a) has the sub-formula (x), (y) or (z) as defined herein    and wherein:-   R¹² and R¹³ independently are H; C₁₋₅alkyl (e.g. C₁₋₃alkyl);    C₃₋₆cycloalkyl; or phenyl optionally substituted by one or two of: a    halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or    C₁fluoroalkoxy;-   or R¹² and R¹³ together are —(CH₂)_(n) ⁶— or —C(O)—(CH₂)_(n) ⁷— or    —C(O)—(CH₂)_(n) ⁷—C(O)— or —(CH₂)_(n) ⁸—X¹²—(CH₂)_(n) ⁹— or    —C(O)—X¹²—(CH₂)_(n) ¹⁰— in which: n⁶ is 3, 4, 5 or 6 (preferably n⁶    is 4 or 5), n⁷ is 2, 3, 4, or 5 (preferably n⁷ is 2, 3 or 4), n⁸ and    n⁹ and n¹⁰ independently are 2 or 3 (independently preferably 2) and    X¹² is O or NR¹⁴ wherein-   R¹⁴ is H or C₁₋₂alkyl;-   R¹⁵ is a hydrogen atom (H); C₁₋₄alkyl (e.g. tBu or C₁₋₂alkyl e.g.    methyl); C₃₋₆cycloalkyl; or phenyl optionally substituted by one or    two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or    C₁fluoroalkoxy,-   R¹⁶ is C₁₋₄alkyl (e.g. C₁₋₂alkyl); C₃₋₆cycloalkyl; pyridinyl (e.g.    pyridin-2-yl); or phenyl optionally substituted by one or two of: a    halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₂alkoxy or C₁fluoroalkoxy;    and-   R¹⁹ is a hydrogen atom (H); C₁₋₄alkyl (e.g. isobutyl, sec-butyl, or    C₁₋₃alkyl such as methyl or isopropyl); —(CH₂)_(n) ²⁰—OR²⁰ wherein    n²⁰ is 1, 2, 3 or 4 (preferably 1) and R²⁰ is a hydrogen atom (H) or    C₁₋₄alkyl (preferably R²⁰ is H); —CH(Me)-OH; —CH₂—SH; —CH₂—CH₂—S-Me;    benzyl; or (4-hydroxyphenyl)methyl (i.e. 4-hydroxy-benzyl).

In formula (IB), preferably, when R³ is the heterocyclic group ofsub-formula (bb), n¹ is 1, and Y is NR¹⁰, then:

-   either (a) R¹⁰ is not C₁₋₄alkyl, C₁₋₂fluoroalkyl or CH₂C(O)NH₂;-   or (b) R¹⁰ is methyl and the compound is:    1-ethyl-N-(2-ethylbutyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide    or    1-ethyl-N-(4-fluorophenyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide.

In formula (IB), preferably, where X is OR^(5a), the compound is otherthan the compound wherein R¹ is methyl, X is OEt, and R³ is cyclopentyl.

In formula (IB), where R³ is optionally substituted C₃₋₈cycloalkyl, theone or two optional substituents preferably comprise (e.g. is or are) OHand/or oxo (═O). In formula (IB), in the R³ heterocyclic group ofsub-formula (aa), (bb) or (cc), the one or two optional substituentspreferably comprise (e.g. is or are) OH and/or oxo.

Examples 1-203 are examples of compounds or salts of the third aspect ofthe invention (Formula (IB)).

The preferred or optional features for the compound or salt of formula(IA) and for the compound or salt of formula (IB) are the same as orsimilar to the preferred or optional features for the compound or saltof formula (I), with all necessary changes (for example to the formula,to the R groups and/or to substituents) having been made. Generally,whenever formula (I) is mentioned herein, then in alternativeembodiments the statement mentioning formula (I) applies to formula (IA)or formula (IB), with all necessary changes having been made.

Salts, Solvates, Isomers, Tautomeric Forms, Molecular Weights, etc.

Because of their potential use in medicine, the salts of the compoundsof formula (I) are preferably pharmaceutically acceptable. Suitablepharmaceutically acceptable salts can include acid or base additionsalts. A pharmaceutically acceptable acid addition salt can be formed byreaction of a compound of formula (I) with a suitable inorganic ororganic acid (such as hydrobromic, hydrochloric, sulfuric, nitric,phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonicacid), optionally in a suitable solvent such as an organic solvent, togive the salt which is usually isolated for example by crystallisationand filtration. A pharmaceutically acceptable acid addition salt of acompound of formula (I) can be for example a hydrobromide,hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate,fumarate, citrate, tartrate, benzoate, p-toluenesulfonate,methanesulfonate or naphthalenesulfonate salt. A pharmaceuticallyacceptable base addition salt can be formed by reaction of a compound offormula (I) with a suitable inorganic or organic base, optionally in asuitable solvent such as an organic solvent, to give the base additionsalt which is usually isolated for example by crystallisation andfiltration. Other suitable pharmaceutically acceptable salts includepharmaceutically acceptable metal salts, for example pharmaceuticallyacceptable alkali-metal or alkaline-earth-metal salts such as sodium,potassium, calcium or magnesium salts; in particular pharmaceuticallyacceptable metal salts of one or more carboxylic acid moieties that maybe present in the the compound of formula (I).

Other non-pharmaceutically acceptable salts, eg. oxalates, may be used,for example in the isolation of compounds of the invention, and areincluded within the scope of this invention.

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the salts of the compounds of formula (I).

Also included within the scope of the invention are all solvates,hydrates and complexes of compounds and salts of the invention.

Certain groups, substituents, compounds or salts included in the presentinvention may be present as isomers. The present invention includeswithin its scope all such isomers, including racemates, enantiomers andmixtures thereof.

Certain of the groups, e.g. heteroaromatic ring systems, included incompounds of formula (I) or their salts may exist in one or moretautomeric forms. The present invention includes within its scope allsuch tautomeric forms, including mixtures.

Especially when intended for oral medicinal use, the compound of formula(I) can optionally have a molecular weight of 1000 or less, for example800 or less, in particular 650 or less or 600 or less. Molecular weighthere refers to that of the unsolvated “free base” compound, that isexcluding any molecular weight contributed by any addition salts,solvent (e.g. water) molecules, etc.

Synthetic Process Routes

The following processes can be used to make the compounds of theinvention:

Most of the following synthetic processes following are exemplified forcompounds of Formula (I) wherein R² is a hydrogen atom (H). However,some or all of these processes can also be used with appropriatemodification, e.g. of starting materials and reagents, for makingcompounds of Formula (I) wherein R² is other than H.

Process A

Compounds of formula (I) where X═OR^(5a), can be prepared according to amethod, for example as described by Yu et. al. in J. Med Chem., 2001,44, 1025-1027, by reaction of a compound of formula (II) with an amineof formula R³NH₂. The reaction is preferably carried out in the presenceof a base such as triethylamine or N,N-diisopropylethylamine, and/or inan organic solvent such as ethanol, dioxane or acetonitrile. Thereaction may require heating e.g. to ca. 60-100° C., for example ca.80-90° C.:

Compounds of formula (II) are also described in the above reference andcan be prepared by reaction of a compound of formula (III) with, forexample, diethylethoxymethylene malonate (where R^(5a)=Et) with heating,followed by reaction with phosphorous oxychloride, again with heating:

Where the desired amino pyrazole of formula (III) is not commerciallyavailable, preparation can be achieved using methods described by Dorganet. al. in J. Chem. Soc., Perkin Trans. 1, (4), 938-42; 1980, byreaction of cyanoethylhydrazine with a suitable aldehyde of formulaR⁴⁰CHO in a solvent such as ethanol, with heating, followed by reductionwith, for example sodium in a solvent such as t-butanol. R⁴⁰ should bechosen so as to contain one less carbon atom than R¹, for exampleR⁴⁰=methyl will afford R¹=ethyl.

In an alternative embodiment of Process A, the 4-chloro substituent inthe compound of formula (II) can be replaced by a halogen atom, such asa bromine atom or preferably a chlorine atom, in a compound of formula(IIA) as defined below. In this embodiment of Process A, the compound offormula (IIA) is reacted with the amine of formula R³NH₂.

Process B

Compounds of formula (I) where X═NR⁴R⁵, can be prepared by reaction of acompound of formula (I) with an amine of formula R³NH₂. The reaction ispreferably carried out in the presence of a base, such as triethylamineor N,N-diisopropylethylamine, and/or in an organic solvent such asethanol, THF, dioxane or acetonitrile. The reaction may require heating,e.g. to ca. 60-100° C. or ca. 80-90° C., for example for 8-48 or 12-24hours:

Compounds of formula (IV) can be prepared in a two step procedure asdescribed by Bare et. al. in J. Med. Chem. 1989, 32, 2561-2573. Thisprocess involves, first, reaction of a compound of formula (V) withthionyl chloride (or another agent suitable for forming an acid chloridefrom a carboxylic acid), either in an organic solvent such as chloroformor TBF, or as a neat solution. This reaction may require heating and thethus-formed intermediate may or may not be isolated. Step two involvesreaction with an amine of formula R⁴R⁵NH, in an organic solvent such asTHF or chloroform and may also involve the use of a base such astriethylamine or diisopropylethyl amine:

Compounds of formula (V) can be prepared by hydrolysis of an ester offormula (II) according to the method described by Yu et. al. in J. Med.Chem., 2001, 44, 1025-1027. This procedure preferably involves reactionwith a base such as sodium hydroxide or potassium hydroxide in a solvente.g. an aqueous solvent such as aqueous ethanol or aqueous dioxane:

In an alternative embodiment of Process B, the 4-chloro substituent inthe compound of formula (IV) can be replaced by a halogen atom, such asa bromine atom or preferably a chlorine atom, in a compound of formula(IVA) as defined below. In this embodiment of Process B, the compound offormula (IVA) is reacted with the amine of formula R³NH₂.

Process C

Compounds of formula (I) can also be prepared according to a method, forexample as described by Bare et. al. in J. Med. Chem. 1989, 32,2561-2573, which involves reaction of a compound of formula (VI), inwhich —O—R³⁵ is a leaving group displaceable by an amine, with an amineof formula R³NH₂. The —O—R³⁵ leaving group can be —O—C₁₋₄alkyl (inparticular —O-Et) or —O—S(O)₂—R³⁷, wherein R³⁷ is C₁₋₈alkyl (e.g.C₁₋₄alkyl or C₁₋₂alkyl such as methyl), C₁₋₆fluoroalkyl (e.g.C₁₋₄fluoroalkyl or C₁₋₂fluoroalkyl such as CF₃ or C₄F₉), or phenylwherein the phenyl is optionally substituted by one or two ofindependently C₁₋₂alkyl, halogen or C₁₋₂alkoxy (such as phenyl or4-methyl-phenyl). The reaction may be carried out with or withoutsolvent and may require heating:

Compounds of formula (VI) (also described in the above reference) can beprepared by reaction of a compound of formula (VII) with a suitablealkylating agent of formula R¹—X, where X is a leaving group such ashalogen. The reaction is preferably carried out in the presence of abase such as potassium carbonate, in an anhydrous solvent such as DMF:

The preparation of compounds of formula VII, e.g. where OR³⁵ is OEt, byoxidative cleavage of compounds of formula VIII is described by Bare et.al. in J. Med. Chem. 1989, 32, 2561-2573 (further referred to Zuleskiet. al. in J. Drug. Metab. Dispos., 1985, 13, 139).

In another embodiment of Process C, the compound of formula (VI) can bereplaced by a compound of formula (VIA), wherein X is NR⁴R⁵ or OR^(5a)as defined herein:

In this embodiment of Process C, the compound of formula (VIA) isreacted with the amine of formula R³NH₂.

Process D:

To form a compound of formula (I) wherein X═NR⁴R⁵, a compound of formula(I) but wherein X═OH (a carboxylic acid, the compound of formula (IX) asdefined below) can be converted into an activated compound of formula(I) but wherein X=a leaving group X¹ substitutable by an amine (acompound of formula (X) as defined below, wherein X¹ is a leaving groupsubstitutable by an amine); and subsequently the activated compound canbe reacted with an amine of formula R⁴R⁵NH:

For example, the activated compound (the compound of formula (X)) can bethe acid chloride i.e. an activated compound of formula (I) but whereinthe leaving group X¹═Cl. This can be formed from the carboxylic acid(X═OH, the compound of formula (DC)) e.g. by reaction with thionylchloride, either in an organic solvent such as chloroform or withoutsolvent. See for example Examples 81-85. Alternatively, the activatedcompound (the compound of formula (X)) can be an activated ester whereinthe leaving group X¹ is

The latter activated compound of formula (X) can be formed from thecarboxylic acid (X═OH, the compound of formula (IX))

either:

-   (a) by reaction of the carboxylic acid with a carbodiimide such as    EDC, which is 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide and is    also 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or a salt    thereof e.g. hydrochloride salt,-   preferably followed by reaction of the resulting product with    1-hydroxybenzotriazole (HOBT); reaction (a) usually being carried    out in the presence of a solvent (preferably anhydrous) such as    dimethyl formamide (DMF) or acetonitrile and/or preferably under    anhydrous conditions and/or usually at room temperature (e.g. about    20 to about 25° C.); or-   (b) by reaction with    2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    tetrafluoroborate (TBTU) or    O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate (HATU), in the presence of a base such as    diisopropylethylamine (iPr₂NEt=DIPEA), and usually in the presence    of a solvent such as dimethyl formamide (DMF) or acetonitrile and/or    preferably under anhydrous conditions and/or usually at room    temperature (e.g. about 20 to about 25° C.).

The carboxylic acid wherein X═OH (the compound of formula (IX) below) isusually prepared by hydrolysis of the corresponding ester of formula (I)wherein X is OR^(5a). This ester can itself be prepared by any ofProcesses A, C, E or F as described herein.

Process D1

This is the same as Process D, but involves reaction of the activatedcompound of formula (X), wherein X¹=a leaving group substitutable by anamine (for example a leaving group as defined herein), with an amine offormula R⁴R⁵NH.

Process E

Compounds of formula (I) can be prepared by reaction of a compound offormula (XI) with an alkylating agent of formula R¹—X³, where X³ is aleaving group displaceable by the 1-position pyrazolopyridine nitrogenatom of the compound of formula (XI):

A suitable alkylating agent of formula R¹—X³ can be used. For example,X³ can be a halogen atom such as a chlorine atom or more preferably abromine or iodine atom, or X³ can be O—S(O)₂—R³⁶ wherein R³⁶ isC₁₋₈alkyl (e.g. C₁₋₄alkyl or C₁₋₂alkyl such as methyl), C₁₋₆fluoroalkyl(e.g. C₁₋₄fluoroalkyl or C₁₋₂fluoroalkyl such as CF₃ or C₄F₉), or phenylwherein the phenyl is optionally substituted by one or two ofindependently C₁₋₂alkyl, halogen or C₁₋₂alkoxy (such as phenyl or4-methyl-phenyl). The reaction is preferably carried out in the presenceof a base; the base can for example comprise or be potassium carbonate,sodium carbonate, sodium hydride, potassium hydride, or a basic resin orpolymer such as polymer-bound2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine.The reaction is preferably carried out in the presence of a solvent,e.g. an organic solvent such as DMF; the solvent is preferablyanhydrous. Examples of alkylation Process E include Examples 183, 185,186 and 354.

For preferable methods of making compounds of formula (XI), see forexample (Reference) Examples 19-20, and Intermediates 48 and 54A.

Process F: Conversion of One Compound of Formula (I) or Salt Thereofinto Another Compound of Formula (I) or Salt Thereof.

One compound of formula (I) or salt thereof can be converted intoanother compound of formula (I) or salt thereof. This conversionpreferably comprises or is one or more of the following processes F1 toF10:

F1. An oxidation process. For example, the oxidation process cancomprise or be oxidation of an alcohol to a ketone (e.g. using Jonesreagent, e.g. see Example 205) or oxidation of an alcohol or a ketone toa carboxylic acid. The oxidation process can e.g. comprise or beconversion of a nitrogen-containing compound of formula (I) or saltthereof to the corresponding N-oxide (e.g. usingmeta-chloroperoxybenzoic acid), for example conversion of apyridine-containing compound to the corresponding pyridine N-oxide (e.g.Examples 210-212).

F2. A reduction process, for example reduction of a ketone or acarboxylic acid to an alcohol.

F3. Acylation, for example acylation of an amine (e.g. Examples 329-349,Example 353) or hydroxy group.

F4. Alkylation, for example alkylation of an amine or of a hydroxygroup.

F5. Hydrolysis, e.g. hydrolysis of an ester to the correspondingcarboxylic acid or salt thereof (e.g. Examples 351, 488, 489, 650, 651).

F6. Deprotection, e.g. deprotection (e.g. deacylation ort-butyloxycarbonyl (BOC) removal) of an amine group (e.g. Examples 320,(321), and (352)).

F7. Formation of an ester or amide, for example from the correspondingcarboxylic acid.

F8. Conversion of a ketone into the corresponding oxime (e.g. Examples652, 653, 654 and 680-686).

F9. Sulfonylation, e.g. sulfonamide formation by reaction of an aminewith a sulfonyl halide e.g. a sulfonyl chloride (e.g. Examples 322-328).and/or

F10. Beckmann rearrangement of one compound of formula (I) into anothercompound of formula (I), preferably using cyanuric chloride(2,4,6-trichloro-1,3,5-triazine) together with a formamide such as DMF,e.g. at room temperature (see L. D. Luca, J. Org. Chem., 2002, 67,6272-6274). The Beckmann rearrangement can for example compriseconversion of a compound of formula (I) wherein NHR³ is of sub-formula(o2)

into a compound of formula (I) wherein NHR³ is of sub-formula

e.g. as illustrated in Examples 658 and 659.

The present invention therefore also provides a method of preparing acompound of formula (I) or a salt thereof:

-   wherein R¹, R² and R³ are as defined herein and X is NR⁴R⁵ or    OR^(5a) as defined herein, the method comprising:-   (a) for a compound of formula (I) wherein X═OR^(5a), reaction of a    compound of formula (IIA):-   wherein Hal is a halogen atom (such as a bromine atom or preferably    a chlorine atom), with an amine of formula R³NH₂, or-   (b) for a compound of formula (I) wherein X═NR⁴R⁵, reaction of a    compound of formula (IVA):-   wherein Hal is a halogen atom (such as a bromine atom or preferably    a chlorine atom), with an amine of formula R³NH₂, or-   (c) reaction of a compound of formula (VIA):    in which —O—R³⁵ is a leaving group displaceable by an amine (such as    —O—C₁₋₄alkyl or —O—S(O)₂—R³⁷),-   with an amine of formula R³NH₂; or-   (d) to form a compound of formula (I) wherein X═NR⁴R⁵, conversion of    a compound of formula (IX) into an activated compound of formula (X)    wherein X¹=a leaving group substitutable by an amine:    and subsequent reaction of the activated compound of formula (X)    with an amine of formula R⁴R⁵NH; or-   (d1) to form a compound of formula (I) wherein X═NR⁴R⁵, reaction of    an activated compound of formula (X) as defined above with an amine    of formula R⁴R⁵NH; or-   (e) reaction of a compound of formula (XI):-   with an alkylating agent of formula R¹—X², where X² is a leaving    group displaceable by the 1-position pyrazolopyridine nitrogen atom    of the compound of formula (XI); or-   (f) conversion of one compound of formula (I) or salt thereof into    another compound of formula (I) or salt thereof;-   and optionally converting the compound of formula (I) into a salt    thereof e.g. a pharmaceutically acceptable salt thereof.

In methods (d) and/or (d1), the activated compound of formula (X)wherein X¹=a leaving group substitutable by an amine can be the acidchloride i.e. an activated compound of formula (X) wherein X¹═Cl.Alternatively, the activated compound of formula (X) can be an activatedester wherein the leaving group X¹ is

Preferred features of methods (a), (b), (c), (d), (d1) and (e),independently of each other, are as described above for Processes A, B,C, D, D1 and E, with all necessary changes being made.

The present invention also provides: (g) a method of preparing apharmaceutically acceptable salt of a compound of formula (I) comprisingconversion of the compound of formula (I) or a salt thereof into thedesired pharmaceutically acceptable salt thereof (See for exampleExamples 490, 491, 518A, 593).

The present invention also provides a compound of formula (I) or a saltthereof, prepared by a method as defined herein.

Medical Uses

The present invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use as an activetherapeutic substance in a mammal such as a human. The compound or saltcan be for use in the treatment and/or prophylaxis of any of thediseases/conditions described herein (e.g. for use in the treatmentand/or prophylaxis of an inflammatory and/or allergic disease in amammal) and/or for use as a phosphodiesterase inhibitor e.g. for use asa phosphodiesterase 4 (PDE4) inhibitor. “Therapy” may include treatmentand/or prophylaxis.

Also provided is the use of a compound of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament (e.g. pharmaceutical composition) for the treatment and/orprophylaxis of any of the diseases/conditions described herein in amammal such as a human, e.g. for the treatment and/or prophylaxis of aninflammatory and/or allergic disease in a mammal such as a human.

Also provided is a method of treatment and/or prophylaxis of any of thediseases/conditions described herein in a mammal (e.g. human) in needthereof, e.g. a method of treatment and/or prophylaxis of aninflammatory and/or allergic disease in a mammal (e.g. human) in needthereof, which method comprises administering to the mammal (e.g. human)a therapeutically effective amount of a compound of formula (I) asherein defined or a pharmaceutically acceptable salt thereof.

Phosphodiesterase 4 inhibitors are thought to be useful in the treatmentand/or prophylaxis of a variety of diseases/conditions, especiallyinflammatory and/or allergic diseases, in mammals such as humans, forexample: asthma, chronic obstructive pulmonary disease (COPD) (e.g.chronic bronchitis and/or emphysema), atopic dermatitis, urticaria,allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis,eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock,ulcerative colitis, Crohn's disease, reperfusion injury of themyocardium and brain, chronic glomerulonephritis, endotoxic shock, adultrespiratory distress syndrome, multiple sclerosis, cognitive impairment(e.g. in a neurological disorder such as Alzheimer's disease),depression, or pain. Ulcerative colitis and/or Crohn's disease arecollectively often referred to as inflammatory bowel disease.

In the treatment and/or prophylaxis, the inflammatory and/or allergicdisease is preferably chronic obstructive pulmonary disease (COPD),asthma, rheumatoid arthritis or allergic rhinitis in a mammal (e.g.human). More preferably, the treatment and/or prophylaxis is of COPD orasthma in a mammal (e.g. human).

PDE4 inhibitors are thought to be effective in the treatment of asthma(e.g. see M. A. Giembycz, Drugs, February 2000, 59(2), 193-212; Z. Huanget al., Current Opinion in Chemical Biology, 2001, 5: 432-438; H. J.Dyke et al., Expert Opinion on Investigational Drugs, January 2002,11(1), 1-13; C. Burnouf et al., Current Pharmaceutical Design, 2002,8(14), 1255-1296; A. M. Doherty, Current Opinion Chem. Biol., 1999,3(4), 466-473; and refs cited therein).

PDE4 inhibitors are thought to be effective in the treatment of COPD(e.g. see S. L. Wolda, Emerging Drugs, 2000, 5(3), 309-319; Z. Huang etal., Current Opinion in Chemical Biology, 2001, 5: 432-438; H. J. Dykeet al., Expert Opinion on Investigational Drugs, January 2002, 11(1),1-13; C. Burnouf et al., Current Pharmaceutical Design, 2002, 8(14),1255-1296; A. M. Doherty, Current Opinion Chem. Biol., 1999, 3(4),466-473; and refs cited therein). COPD is often characterised by thepresence of airflow obstruction due to chronic bronchitis and/oremphysema (S. L. Wolda, Emerging Drugs, 2000, 5(3), 309-319).

PDE4 inhibitors are thought to be effective in the treatment of allergicrhinitis (e.g. see B. M. Schmidt et al., J. Allergy & ClinicalImmunology, 108(4), 2001, 530-536).

PDE4 inhibitors are thought to be effective in the treatment ofrheumatoid arthritis and multiple sclerosis (e.g. see H. J. Dyke et al.,Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C.Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296;and A. M. Doherty, Current Opinion Chem. Biol., 1999, 3(4), 466-473; andrefs cited therein). See e.g. A. M. Doherty, Current Opinion Chem.Biol., 1999, 3(4), 466-473 and refs cited therein for atopic dermatitisuse.

PDE4 inhibitors have been suggested as having analgesic properties andthus being effective in the treatment of pain (A. Kumar et al., IndianJ. Exp. Biol., 2000, 38(1), 26-30).

In the invention, the treatment and/or prophylaxis can be of cognitiveimpairment e.g. cognitive impairment in a neurological disorder such asAlzheimer's disease. For example, the treatment and/or prophylaxis cancomprise cognitive enhancement e.g. in a neurological disorder. See forexample: H. T. Zhang et al. in: Psychopharmacology, June 2000, 150(3),311-316 and Neuropsychopharmacology, 2000, 23(2), 198-204; and T. Egawaet al., Japanese J. Pharmacol., 1997, 75(3), 275-81.

PDE4 inhibitors such as rolipram have been suggested as havingantidepressant properties (e.g. J. Zhu et al., CNS Drug Reviews, 2001,7(4), 387-398; O'Donnell, Expert Opinion on Investigational Drugs, 2000,9(3), 621-625; and H. T. Zhang et al., Neuropsychopharmacology, October2002, 27(4), 587-595).

Pharmaceutical Compositions and Dosing

For use in medicine, the compounds of the present invention are usuallyadministered as a pharmaceutical composition.

The present invention therefore provides in a further aspect apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers and/or excipients.

The pharmaceutical composition can be for use in the treatment and/orprophylaxis of any of the conditions described herein.

The invention also provides a method of preparing a pharmaceuticalcomposition comprising a compound of formula (I), as herein defined, ora pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers and/or excipients,

-   -   the method comprising mixing the compound or salt with the one        or more pharmaceutically acceptable carriers and/or excipients.

The invention also provides a pharmaceutical composition prepared bysaid method.

The compounds of formula (I) and/or the pharmaceutical composition maybe administered, for example, by oral, parenteral (e.g. intravenous,subcutaneous, or intramuscular), inhaled or nasal administration.Accordingly, the pharmaceutical composition is preferably suitable fororal, parenteral (e.g. intravenous, subcutaneous, or intramuscular),inhaled or nasal administration. More preferably, the pharmaceuticalcomposition is suitable for inhaled or oral administration, e.g. to amammal such as a human. Inhaled administration involves topicaladministration to the lung e.g. by aerosol or dry powder composition.Oral administration to a human is most preferred.

A pharmaceutical composition suitable for oral administration can beliquid or solid; for example it can be a syrup, suspension or emulsion,a tablet, a capsule or a lozenge.

A liquid formulation will generally consist of a suspension or solutionof the compound or pharmaceutically acceptable salt in a suitablepharmaceutically acceptable liquid carrier(s), for example an aqueoussolvent such as water, ethanol or glycerine, or a non-aqueous solvent,such as polyethylene glycol or an oil. The formulation may also containa suspending agent, preservative, flavouring and/or colouring agent.

A pharmaceutical composition suitable for oral administration being atablet can comprise one or more pharmaceutically acceptable carriersand/or excipients suitable for preparing tablet formulations. Examplesof such carriers include lactose and cellulose. The tablet can also orinstead contain one or more pharmaceutically acceptable excipients, forexample binding agents, lubricants such as magnesium stearate, and/ortablet disintegrants.

A pharmaceutical composition suitable for oral administration being acapsule can be prepared using encapsulation procedures. For example,pellets containing the active ingredient can be prepared using asuitable pharmaceutically acceptable carrier and then filled into a hardgelatin capsule. Alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutically acceptable carrier, forexample an aqueous gum or an oil and the dispersion or suspension thenfilled into a soft gelatin capsule.

Preferably the composition is in unit dose form such as a tablet orcapsule for oral administration, e.g. for oral administration to ahuman.

A parenteral composition can comprise a solution or suspension of thecompound or pharmaceutically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil. Alternatively, the solution canbe lyophilised; the lyophilised parenteral pharmaceutical compositioncan be reconstituted with a suitable solvent just prior toadministration.

Compositions for nasal or inhaled administration may conveniently beformulated as aerosols, drops, gels or dry powders.

Aerosol formulations, e.g. for inhaled administration, can comprise asolution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent. Aerosolformulations can be presented in single or multidose quantities insterile form in a sealed container, which can take the form of acartridge or refill for use with an atomising device or inhaler.Alternatively the sealed container may be a unitary dispensing devicesuch as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve (metered dose inhaler) which is intended for disposalonce the contents of the container have been exhausted.

Where the dosage form comprises an aerosol dispenser, it preferablycontains a suitable propellant under pressure such as compressed air,carbon dioxide, or an organic propellant such as a chlorofluorocarbon(CFC) or hydrofluorocarbon (HFC). Suitable CFC propellants includedichlorodifluoromethane, trichlorofluoromethane anddichlorotetrafluoroethane. Suitable HFC propellants include1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2-tetrafluoroethane. Theaerosol dosage forms can also take the form of a pump-atomiser.

For pharmaceutical compositions suitable and/or adapted for inhaledadministration, it is preferred that the compound or salt of formula (I)is in a particle-size-reduced form, and more preferably the size-reducedform is obtained or obtainable by micronisation. Micronisation usuallyinvolves subjecting the compound/salt to collisional and abrasionalforces in a fast-flowing circular or spiral/vortex-shaped airstreamoften including a cyclone component. The preferable particle size (e.g.D50 value) of the size-reduced (e.g. micronised) compound or salt isabout 0.5 to about 10 microns, e.g. about 1 to about 5 microns (e.g. asmeasured using laser diffraction). For example, it is preferable for thecompound or salt of formula (I to have a particle size defined by: a D10of about 0.3 to about 3 microns (e.g. about 1 micron), and/or a D50 ofabout 1 to about 5 microns (e.g. about 2-5 or about 2-3 microns), and/ora D90 of about 2 to about 20 microns or about 3 to about 10 microns(e.g. about 5-8 or about 5-6 microns); for example as measured usinglaser diffraction. The laser diffraction measurement can use a drymethod (suspension of compound/salt in airflow crosses laser beam) or awet method [suspension of compound/salt in liquid dispersing medium,such as isooctane or (e.g. if compound soluble in isooctane) 0.1% Tween80 in water, crosses laser beam]. With laser diffraction, particle sizeis preferably calculated using the Fraunhofer calculation; and/orpreferably a Malvern Mastersizer or Sympatec apparatus is used formeasurement.

An illustrative non-limiting example of a small-scale micronisationprocess is now given:

Micronisation Example: Micronisation of Example 518 or 518A

-   -   Purpose: To micronize approximately 600-1000 mg of Example 518        or 518A (described hereinafter) using a Jetpharma MC1        micronizer.    -   The parent (unmicronised) and micronised materials are analyzed        for particle size by laser diffraction and crystallinity by        PXRD.

Equipment and Material Equipment/material Description and specificationJetpharma MC1 Micronizer Nitrogen supply: Air tank with 275 psi ratetubing Analytical balance Sartorius Analytical Top loader balanceMettler PM400 Digital Caliper VWR Electronic caliper Vibrational spatulaAuto-spat Dispenser Materials to be micronised Example 518 or 518A

The Jetpharma MC1 Micronizer comprises a horizontal disc-shaped millinghousing having: a tubular compound inlet (e.g. angled at ca. 30 degreesto the horizontal) for entry of a suspension of unmicronised compound offormula (I) or salt in an gasflow, a separate gas inlet for entry ofgases, a gas outlet for exit of gases, and a collection vessel forcollecting micronised material. The milling housing has two chambers: anouter annular chamber in gaseous connection with the gas inlet thechamber being for receiving pressurised gas (e.g. air or nitrogen), andisc-shaped inner milling chamber within and coaxial with the outerchamber for micronising the input compound/salt, the two chambers beingseparated by an annular wall. The annular wall (ring R) has a pluralityof narrow-bored holes connecting the inner and outer chambers andcircumferentially-spaced-apart around the annular wall. The holes openinto the inner chamber directed at an angle (directed part-way betweenradially and tangentially), and in use act as nozzles directingpressurised gas at high velocity from the outer chamber into the innerchamber and in an inwardly-spiral path (vortex) around the inner chamber(cyclone). The compound inlet is is gaseous communication with the innerchamber via a nozzle directed tangentially to the inner chamber, withinand near to the annular wall. Upper and lower broad-diameter exit ventsin the central axis of the the inner milling chamber connect to (a)(lower exit) the collection vessel which has no air outlet, and (b)(upper exit) the gas outlet which leads to a collection bag, filter anda gas exhaust. Inside the tubular compound inlet andlongitudinally-movable within it is positioned a venturi inlet (V) forentry of gases. The compound inlet also has a bifurcation connecting toan upwardly-directed material inlet port for inputting material.

In use, the narrow head of the venturi inlet (V) is preferablypositioned below and slightly forward of the material inlet port so thatwhen the venturi delivers pressurised gas (eg air or nitrogen) the feedmaterial is sucked into the gasstream thorough the compound inlet andaccelerates it into the inner milling chamber tangentially at a subsonicspeed. Inside the milling chamber the material is further accelerated toa supersonic speed by the hole/nozzle system around the ring (R)(annular wall) of the milling chamber. The nozzles are slightly angledso that the acceleration pattern of the material is in the form of aninwardly-directed vortex or cyclone. The material inside the millingchamber circulates rapidly and particle collisions occur during theprocess, causing larger particles to fracture into smaller ones.“Centrifugal” acceleration in the vortex causes the larger particles toremain at the periphery of the inner chamber while progressively smallerparticles move closer to the center until they exit the milling chamber,generally through the lower exit, at low pressure and low velocity. Theparticles that exit the milling chamber are heavier than air and settledownward thorugh the lower exit into the collection vessel, while theexhaust gas rises (together with a minority of small particles ofmicronised material) and escapes into the atmosphere at low pressure andlow velocity.

Procedure:

The micronizer is assembled. The venturi protrusion distance from inputport is adjusted to 1.0 cm respectively (e.g. so that the narrow head ofthe venturi inlet is positioned below and slightly forward of thematerial inlet port) and is measured with a micro-caliper to make surethat it is inserted correctly. The ring (R) and venturi (V) pressuresare adjusted according to the values specified in the experimentaldesign (refer to experimental section below) by adjusting the valves onthe pressure gauges on the micronizer. The setup is checked for leakageby observing if there is any fluctuation in the reading of the pressuregauges.

Note that the venturi (V) pressure is kept at least 2 bars greater thanthe ring (R) pressure to prevent regurgitation of material, e.g.outwardly from the material inlet port.

Balance performance is checked with calibration weights. Specifiedamount of the parent material (see section on experimental run) isweighed into a plastic weigh boat.

The material is then fed into the micronizer using a vibrational spatula(e.g. V-shaped in cross-section) at a specified feed rate. The materialfeeding time and equipment pressures are monitored during themicronization process.

Upon completion of the micronising run, the nitrogen supply is shut offand the collection bag is tapped to allow particles to settle into therecovery/collection vessel at the bottom of the micronizer. Thecollection bag is removed and set aside. The micronised powder in therecovery vessel (collection vessel) and the cyclone (above the recoveryvessel) are collected separately into different weighed+labelledcollection vials. The weight of the micronised material is recorded. Themicronizer is disassembled and residual PDE4 compound on the micronizerinner surface is rinsed with 70/30 isopropyl alcohol/water and collectedinto a flask. The micronizer is then thoroughly cleaned by rinsing andwiping with suitable solvent and dried before subsequent runs areperformed.

Preferred Experimental Parameters

-   Parent (unmicronised) material (Procedure 1): Example 518 or 518A-   Parent (unmicronised) material (Procedure 2): Example 518-   Balance(s) Used: Sartorius analytical

Venturi outlet insertion depth: 10.0 mm Time Venturi (V)/ needed toMaterial ring (R) feed Procedure input Pressure Intended material Actualfeed-rate no. amount (g) (bar) feed-rate (min + sec) (g/min) 1 0.8795 gV = 10 bar 200 mg/min 4 min 51 sec 181 mg/min R = 6 bar 2 0.9075 g V = 8bar 200 mg/min 4 min 43 sec 192 mg/min R = 5.5 bar

The above parameters can be varied using the skilled person's knowledge.

Results and/or Observations% yield=[(Material from vessel+Material from cyclone)/Material inputamount]×100

In general, very approximately 50-75% yields are achievable using thismethod. Procedure 1 has not been completed.

In Procedure 2, a 70.8% yield (0.6427 g) of Example 518 micronisedmaterial was obtained, including material from collection vessel andmaterial from inside walls of cyclone.

Particle size analysis of Example 518 micronised material from Procedure2, using laser diffraction measurement with Malvern Mastersizer longbedversion, dispersing medium 0.1% Tween 80 in water, stir rate 1500 rpm, 3mins sonification prior to final dispersion and analysis, 300 RF ReverseFourier) lens, Fraunhofer calculation with Malvern software:

-   -   material from collection vessel: D10=0.97 microns, D50=3.86        microns, D90=12.64 microns.    -   material from inside walls of cyclone: D10=0.95 microns,        D50=3.42 microns, D90=9.42 microns.

Alternative embodiment: Examples of the compounds/salts of the inventionother than Examples 518 or 518A can be micronised.

For pharmaceutical compositions suitable and/or adapted for inhaledadministration, it is preferred that the pharmaceutical composition is adry powder inhalable composition. Such a composition can comprise apowder base such as lactose or starch, the compound of formula (I) orsalt thereof (preferably in particle-size-reduced form, e.g. inmicronised form), and optionally a performance modifier such asL-leucine, mannitol, trehalose and/or magnesium stearate. Preferably,the dry powder inhalable composition comprises a dry powder blend oflactose and the compound of formula (I) or salt thereof. The lactose ispreferably lactose hydrate e.g. lactose monohydrate and/or is preferablyinhalation-grade and/or fine-grade lactose. Preferably, the particlesize of the lactose is defined by 90% or more (by weight or by volume)of the lactose particles being less than 1000 microns (micrometres)(e.g. 10-1000 microns e.g. 30-1000 microns) in diameter, and/or 50% ormore of the lactose particles being less than 500 microns (e.g. 10-500microns) in diameter. More preferably, the particle size of the lactoseis defined by 90% or more of the lactose particles being less than 300microns (e.g. 10-300 microns e.g. 50-300 microns) in diameter, and/or50% or more of the lactose particles being less than 100 microns indiameter. Optionally, the particle size of the lactose is defined by 90%or more of the lactose particles being less than 100-200 microns indiameter, and/or 50% or more of the lactose particles being less than40-70 microns in diameter. Most importantly, it is preferable that about3 to about 30% (e.g. about 10%) (by weight or by volume) of theparticles are less than 50 microns or less than 20 microns in diameter.For example, without limitation, a suitable inhalation-grade lactose isE9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017JD Zwolle, Netherlands).

In the dry powder inhalable composition, preferably, the compound offormula (I) or salt thereof is present in about 0.1% to about 70% (e.g.about 1% to about 50%, e.g. about 5% to about 40%, e.g. about 20 toabout 30%) by weight of the composition.

An illustrative non-limiting example of a dry powder inhalablecomposition follows:

Dry Powder Formulation Example—Dry powder Lactose Blend Preparation

Using a size-reduced e.g. micronised form of the compound of formula (I)or salt thereof (e.g. as prepared in the Micronisation Example above),the dry powder blend is prepared by mixing the required amount of thecompound/salt (e.g. 10 mg, 1% w/w) with inhalation-grade lactosecontaining 10% fines (e.g. 990 mg, 99% w/w) in a Teflon™(polytetrafluoroethene) pot in a Mikro-dismembrator ball-mill (butwithout a ball bearing) at ¾ speed (ca. 2000-2500 rpm) for about 4 hoursat each blend concentration. The Mikro-dismembrator (available from B.Braun Biotech International, Schwarzenberger Weg 73-79, D-34212Melsungen, Germany; www.bbraunbiotech.com) comprises a base with anupwardly-projecting and sidewardly-vibratable arm to which is attachedthe Teflon™ pot. The vibration of the arm achieves blending.

Other blends: 10% w/w compound/salt (50 mg)+90% w/w lactose (450 mg,inhalation-grade lactose containing 10% fines).

Serial dilution of the 1% w/w blend can achieve e.g. 0.1% and 0.3% w/wblends.

Optionally, in particular for dry powder inhalable compositions, apharmaceutical composition for inhaled administration can beincorporated into a plurality of sealed dose containers (e.g. containingthe dry powder composition) mounted longitudinally in a strip or ribboninside a suitable inhalation device. The container is rupturable orpeel-openable on demand and the dose, e.g. of the dry powdercomposition, can be administered by inhalation via a device such as theDISKUS™ device, marketed by GlaxoSmithKline. The DISKUS™ inhalationdevice is usually substantially as described in GB 2,242,134 A. In suchdevice at least one container for the pharmaceutical composition inpowder form (the at least one container preferably being a plurality ofsealed dose containers mounted longitudinally in a strip or ribbon) isdefined between two members peelably secured to one another; the devicecomprises: means defining an opening station for the said at least onecontainer; means for peeling the members apart at the opening station toopen the container; and an outlet, communicating with the openedcontainer, through which a user can inhale the pharmaceuticalcomposition in powder form from the opened container.

In the pharmaceutical composition, a or each dosage unit for oral orparenteral administration preferably contains from 0.01 to 3000 mg, morepreferably 0.5 to 1000 mg, of a compound of the formula (I) or apharmaceutically acceptable salt thereof, calculated as the free base. Aor each dosage unit for nasal or inhaled administration preferablycontains from 0.001 to 50 mg, more preferably 0.01 to 5 mg, of acompound of the formula (I) or a pharmaceutically acceptable saltthereof, calculated as the free base.

A pharmaceutically acceptable compound or salt of the invention ispreferably administered to a mammal (e.g. human) in a daily oral orparenteral dose of 0.001 mg to 50 mg per kg body weight per day(mg/kg/day), for example 0.01 to 20 mg/kg/day or 0.03 to 10 mg/kg/day or0.1 to 2 mg/kg/day, of the compound of the formula (I) or apharmaceutically acceptable salt thereof, calculated as the free base.

A pharmaceutically acceptable compound or salt of the invention ispreferably administered to a mammal (e.g. human) in a daily nasal orinhaled dose of: 0.0001 to 5 mg/kg/day or 0.0001 to 1 mg/kg/day, e.g.0.001 to 1 mg/kg/day or 0.001 to 0.3 mg/kg/day or 0.001 to 0.1 mg/kg/dayor 0.005 to 0.3 mg/kg/day, of the compound of the formula (I) or apharmaceutically acceptable salt thereof, calculated as the free base.

The pharmaceutically acceptable compounds or salts of the invention ispreferably administered in a daily dose (for an adult patient) of, forexample, an oral or parenteral dose of 0.01 mg to 3000 mg per day or 0.5to 1000 mg per day e.g. 2 to 500 mg per day, or a nasal or inhaled doseof 0.001 to 300 mg per day or 0.001 to 50 mg per day or 0.01 to 30 mgper day or 0.01 to 5 mg per day or 0.02 to 2 mg per day, of the compoundof the formula (I) or a pharmaceutically acceptable salt thereof,calculated as the free base.

Combinations

The compounds, salts and/or pharmaceutical compositions according to theinvention may also be used in combination with another therapeuticallyactive agent, for example, a β₂ adrenoreceptor agonist, ananti-histamine, an anti-allergic or an anti-inflammatory agent.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with another therapeutically active agent, forexample, a β₂-adenoreceptor agonist, an anti-histamine, ananti-allergic, an anti-inflammatory agent or an antiinfective agent.

Preferably, the β₂-adrenoreceptor agonist is salmeterol (e.g. asracemate or a single enantiomer such as the R-enantiomer), salbutamol,formoterol, salmefamol, fenoterol or terbutaline, or a salt thereof(e.g. pharmaceutically acceptable salt thereof), for example thexinafoate salt of salmeterol, the sulphate salt or free base ofsalbutamol or the fumarate salt of formoterol. Long-actingβ₂-adrenoreceptor agonists are preferred, especially those having atherapeutic effect over a 12-24 hour period such as salmeterol orformoterol. Preferably, the β₂-adrenoreceptor agonist is for inhaledadministration, e.g. once per day and/or for simultaneous inhaledadministration; and more preferably the β₂-adrenoreceptor agonist is inparticle-size-reduced form e.g. as defined herein. Preferably, theβ₂-adrenoreceptor agonist combination is for treatment and/orprophylaxis of COPD or asthma. Salmeterol or a pharmaceuticallyacceptable salt thereof, e.g. salmeterol xinofoate, is preferablyadministered to humans at an inhaled dose of 25 to 50 micrograms twiceper day (measured as the free base). The combination with aβ₂-adrenoreceptor agonist can be as described in WO 00/12078.

Preferred long acting β₂-adrenoreceptor agonists include those describedin WO 02/066422A, WO 03/024439, WO 02/070490 and WO 02/076933.

Especially preferred long-acting β₂-adrenoreceptor agonists includecompounds of formula (XX) (described in WO 02/066422):

-   or a salt or solvate thereof, wherein in formula (XX):-   m^(x) is an integer of from 2 to 8;-   n^(x) is an integer of from 3 to 11,-   with the proviso that m^(x)+n^(x) is 5 to 19,-   R^(11X) is —XSO₂NR^(16X)R^(17X) wherein X is —(CH₂)_(p) ^(x)— or    C₂₋₆ alkenylene;-   R^(16X) and R^(17X) are independently selected from hydrogen,    C₁₋₆alkyl, C₃₋₇cycloalkyl, C(O)NR^(18X)R^(19X), phenyl, and phenyl    (C₁₋₄alkyl)-, or R^(16X) and R^(17X), together with the nitrogen to    which they are bonded, form a 5-, 6-, or 7-membered nitrogen    containing ring, and R^(16X) and R^(17X) are each optionally    substituted by one or two groups selected from halo, C₁₋₆alkyl,    C₁₋₆haloalkyl, C₁₋₆alkoxy, hydroxy-substituted C₁₋₆alkoxy,    —CO₂R^(18X), —SO₂NR^(18X)R^(19X), —CONR^(18X)R^(19X),    —NR^(18X)C(O)R^(19X), or a 5-, 6- or 7-membered heterocylic ring;-   R^(18X) and R^(19X) are independently selected from hydrogen,    C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, and phenyl (C₁₋₄alkyl)-; and-   p^(X) is an integer of from 0 to 6, preferably from 0 to 4;-   R^(12X) and R^(13X) are independently selected from hydrogen,    C₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyl, and C₁₋₆haloalkyl; and-   R^(14X) and R^(15X) are independently selected from hydrogen and    C₁₋₄alkyl with the proviso that the total number of carbon atoms in    R^(14X) and R^(15X) is not more than 4.

Preferred β₂-adrenoreceptor agonists disclosed in WO 02/066422 include:

-   3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide    and-   3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide.

A preferred β₂-adrenoreceptor agonist disclosed in WO 03/024439 is:

-   4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol.

A combination of a compound of formula (I) or salt together with ananti-histamine is preferably for oral administration (e.g. as a combinedcomposition such as a combined tablet), and can be for treatment and/orprophylaxis of allergic rhinitis. Examples of anti-histamines includemethapyrilene, or H1 antagonists such as cetirizine, loratadine (e.g.Clarityn™), desloratadine (e.g. Clarinex™) or fexofenadine (e.g.Allegra™).

The invention also provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with an anticholinergic compound, e.g. amuscarinic (M) receptor antagonist in particular an M₁, M₂, M₁/M₂, or M₃receptor antagonist, more preferably a M₃ receptor antagonist, stillmore preferably a M₃ receptor antagonist which selectively antagonises(e.g. antagonises 10 times or more strongly) the M₃ receptor over the M₁and/or M₂ receptor. For combinations of anticholinergiccompounds/muscarinic (M) receptor antagonist with PDE4 inhibitors, seefor example WO 03/011274 A2 and WO 02/069945 A2/US 2002/0193393 A1 andU.S. 2002/052312 A1, and some or all of these publications give examplesof anticholinergic compounds/muscarinic (M) receptor antagonists whichmay be used with the compounds of formula (I) or salts, and/or suitablepharmaceutical compositions. For example, the muscarinic receptorantagonist can comprise or be an ipratropium salt (e.g. ipratropiumbromide), an oxitropium salt (e.g. oxitropium bromide), or morepreferably a tiotropium salt (e.g. tiotropium bromide); see e.g. EP 418716 A1 for tiotropium.

The anticholinergic compound or muscarinic (M) receptor antagonist, e.g.M₃ receptor antagonist, is preferably for inhaled administration, morepreferably in particle-size-reduced form e.g. as defined herein. Morepreferably, both the muscarinic (M) receptor antagonist and the compoundof formula (I) or the pharmaceutically acceptable salt thereof are forinhaled administration. Preferably, the anticholinergic compound ormuscarinic receptor antagonist and the compound of formula (I) or saltare for simultaneous administration. The muscarinic receptor antagonistcombination is preferably for treatment and/or prophylaxis of COPD.

Other suitable combinations include, for example, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with another anti-inflammatory agent such as ananti-inflammatory corticosteroid; or a non-steroidal anti-inflammatorydrug (NSAID) such as a leukotriene antagonist (e.g. montelukast), aniNOS inhibitor, a tryptase inhibitor, a elastase inhibitor, a beta-2integrin antagonist, a adenosine 2a agonist, a CCR3 antagonist, or a5-lipoxogenase inhibitor); or an antiinfective agent (e.g. an antibioticor antiviral). An iNOS inhibitor is preferably for oral administration.Suitable iNOS inhibitors (inducible nitric oxide synthase inhibitors)include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO95/34534 and WO 99/62875. Suitable CCR3 inhibitors include thosedisclosed in WO 02/26722.

In a combination comprising a compound of formula (I) or apharmaceutically acceptable salt thereof together with ananti-inflammatory corticosteroid (which is preferably for treatmentand/or prophylaxis of asthma, COPD or allergic rhinitis), thenpreferably the anti-inflammatory corticosteroid is fluticasone,fluticasone propionate (e.g. see U.S. Pat. No. 4,335,121),beclomethasone, beclomethasone 17-propionate ester, beclomethasone17,21-dipropionate ester, dexamethasone or an ester thereof, mometasoneor an ester thereof, ciclesonide, budesonide, flunisolide, or a compoundas described in WO 02/12266 A1 (e.g. as claimed in any of claims 1 to 22therein), or a pharmaceutically acceptable salt of any of the above. Ifthe anti-inflammatory corticosteroid is a compound as described in WO02/12266 A1, then preferably it is Example 1 therein {which is6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester}or Example 41 therein {which is6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester}, or a pharmaceutically acceptable saltthereof. The anti-inflammatory corticosteroid is preferably forintranasal or inhaled administration. Fluticasone propionate ispreferred and is preferably for inhaled administration to a human either(a) at a dose of 250 micrograms once per day or (b) at a dose of 50 to250 micrograms twice per day.

Also provided is a combination comprising a compound of formula (D) or apharmaceutically acceptable salt thereof together with β₂-adrenoreceptoragonist and an anti-inflammatory corticosteroid, for example asdescribed in WO 03/030939 A1. Preferably this combination is fortreatment and/or prophylaxis of asthma, COPD or allergic rhinitis. Theβ₂-adrenoreceptor agonist and/or the anti-inflammatory corticosteroidcan be as described above and/or as described in WO 03/030939 A1. Mostpreferably, in this “triple” combination, the β₂-adrenoreceptor agonistis salmeterol or a pharmaceutically acceptable salt thereof (e.g.salmeterol xinafoate) and the anti-inflammatory corticosteroid isfluticasone propionate.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical composition and thus a pharmaceuticalcomposition comprising a combination as defined above together with oneor more pharmaceutically acceptable carriers and/or excipients representa further aspect of the invention.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalcomposition.

In one embodiment, the combination as defined herein can be forsimultaneous inhaled administration and is disposed in a combinationinhalation device. Such a combination inhalation device is anotheraspect of the invention. Such a combination inhalation device cancomprise a combined pharmaceutical composition for simultaneous inhaledadministration (e.g. dry powder composition), the composition comprisingall the individual compounds of the combination, and the compositionbeing incorporated into a plurality of sealed dose containers mountedlongitudinally in a strip or ribbon inside the inhalation device, thecontainers being rupturable or peel-openable on demand; for example suchinhalation device can be substantially as described in GB 2,242,134 A(DISKUS™) and/or as described above. Alternatively, the combinationinhalation device can be such that the individual compounds of thecombination are administrable simultaneously but are stored separately(or wholly or partly stored separately for triple combinations), e.g. inseparate pharmaceutical compositions, for example as described inPCT/EP03/00598 filed on 22 Jan. 2003 (e.g. as described in the claimsthereof e.g. Claim 1).

The invention also provides a method of preparing a combination asdefined herein,

-   -   the method comprising either    -   (a) preparing a separate pharmaceutical composition for        administration of the individual compounds of the combination        either sequentially or simultaneously, or    -   (b) preparing a combined pharmaceutical composition for        administration of the individual compounds of the combination        simultaneously,    -   wherein the pharmaceutical composition comprises the combination        together with one or more pharmaceutically acceptable carriers        and/or excipients.

The invention also provides a combination as defined herein, prepared bya method as defined herein.

Biological Test Methods

PDE 3, PDE 4B, PDE 4D, PDE 5, PDE 6 Primary Assay Methods

The activity of the compounds can be measured in the assay methods shownbelow. Preferred compounds of the invention are selective PDE4inhibitors, i.e. they inhibit PDE4 (e.g. PDE4B and/or PDE4D, preferablyPDE4B) more strongly than they inhibit PDE3 and/or more strongly thanthey inhibit PDE5 and/or more strongly than they inhibit PDE6.

PDE Enzyme Sources and Literature References

Human recombinant PDE4B, in particular the 2B splice variant thereof(HSPDE4B2B), is disclosed in WO 94/20079 and also M. M. McLaughlin etal., “A low Km, rolipram-sensitive, cAMP-specific phosphodiesterase fromhuman brain: cloning and expression of cDNA, biochemicalcharacterisation of recombinant protein, and tissue distribution ofmRNA”, J. Biol. Chem., 1993, 268, 6470-6476. For example, in Example 1of WO 94/20079, human recombinant PDE4B is described as being expressedin the PDE-deficient yeast Saccharomyces cerevisiae strain GL62, e.g.after induction by addition of 150 uM CuSO₄, and 100,000×g supernatantfractions of yeast cell lysates are described for use in the harvestingof PDE4B enzyme.

Human recombinant PDE4D (HSPDE4D3A) is disclosed in P. A. Baecker etal., “Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMPphoshodiesterase (PDE IV_(D))”, Gene, 1994, 138, 253-256.

Human recombinant PDE5 is disclosed in K. Loughney et al., “Isolationand characterisation of cDNAs encoding PDE5A, a human cGMP-binding,cGMP-specific 3′,5′-cyclic nucleotide phosphodiesterase”, Gene, 1998,216, 139-147.

PDE3 was purified from bovine aorta as described by H. Coste and P.Grondin, “Characterisation of a novel potent and specific inhibitor oftype V phosphodiesterase”, Biochem. Pharmacol., 1995, 50, 1577-1585.

PDE6 was purified from bovine retina as described by: P. Catty and P.Deterre, “Activation and solubilization of the retinal cGMP-specificphosphodiesterase by limited proteolysis”, Eur. J. Biochem., 1991, 199,263-269; A. Tar et al. “Purification of bovine retinal cGMPphosphodiesterase”, Methods in Enzymology, 1994, 238, 3-12; and/or D.Srivastava et al. “Effects of magnesium on cyclic GMP hydrolysis by thebovine retinal rod cyclic GMP phosphodiesterase”, Biochem. J., 1995,308, 653-658.

Inhibition of PDE 3, PDE 4B, PDE 4D, PDE 5 or PDE 6 activity:radioactive Scintillation Proximity Assay (SPA)

The ability of compounds to inhibit catalytic activity at PDE4B or 4D(human recombinant), PDE3 (from bovine aorta), PDE5 (human recombinant)or PDE6 (from bovine retina) was determined by Scintillation ProximityAssay (SPA) in 96-well format. Test compounds (preferably as a solutionin DMSO, e.g. 0.5 to 1 microlitre (ul) volume) were preincubated atambient temperature (room temperature, e.g. 19-23° C.) in WallacIsoplates (code 1450-514) with PDE enzyme in 50 mM Tris-HCl buffer pH7.5, 8.3 mM MgCl₂, 1.7 mM EGTA, 0.05% (w/v) bovine serum albumin for10-30 minutes (usually 30 minutes). The enzyme concentration wasadjusted so that no more than 20% hydrolysis of the substrate definedbelow occurred in control wells without compound, during the incubation.For the PDE3, PDE4B and PDE4D assays, [5′,8-³H]Adenosine 3′,5′-cyclicphosphate (Amersham Pharmacia Biotech, code TRK.559; or AmershamBiosciences UK Ltd, Pollards Wood, Chalfont St Giles, BuckinghamshireHP8 4SP, UK) was added to give 0.05 uCi per well and ˜10 nM finalconcentration. For the PDE5 and PDE6 assays, [8-³H]Guanosine3′,5′-cyclic phosphate (Amersham Pharmacia Biotech, code TRK.392) wasadded to give 0.05 uCi per well and ˜36 nM final concentration. Plates,e.g. containing approx. 100 ul volume of assay mixture, were mixed on anorbital shaker for 5 minutes and incubated at ambient temperature for 1hour. Phosphodiesterase SPA beads (Amersham Pharmacia Biotech, code RPNQ0150) were added (−1 mg per well) to terminate the assay. Plates weresealed and shaken and allowed to stand at ambient temperature for 35minutes to 1 hour (preferably 35 minutes) to allow the beads to settle.Bound radioactive product was measured using a WALLAC TRILUX 1450Microbeta scintillation counter. For inhibition curves, 10concentrations (1.5 nM-30 uM) of each compound were assayed. Curves wereanalysed using ActivityBase and XLfit (ID. Business Solutions Limited, 2Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, UnitedKindgom) Results were expressed as pIC₅₀ values.

In an alternative to the above radioactive SPA assay, PDE4B or PDE4Dinhibition can be measured in the following Fluorescence Polarisation(FP) assay:

Inhibition of PDE4B or PDE4D Activity: Fluorescence Polarisation (FP)Assay

The ability of compounds to inhibit catalytic activity at PDE4B (humanrecombinant) or PDE4D (human recombinant) was determined by IMAPFluorescence Polarisation (PP) assay (IMAP Explorer kit, available fromMolecular Devices Corporation, Sunnydale, Calif., USA; Molecular Devicescode: R⁸⁰⁶²) in 384-well format. The IMAP FP assay is able to measurePDE activity in an homogenous, non-radioactive assay format. The FPassay uses the ability of immobilised trivalent metal cations, coatedonto nanoparticles (tiny beads), to bind the phosphate group of Fl-AMPthat is produced on the hydrolysis of fluorescein-labelled (Fl) cyclicadenosine mono-phosphate (Fl-cAMP) to the non-cyclic Fl-AMP form.Fl-cAMP does not bind. Binding of Fl-AMP product to the beads (coatedwith the immobilised trivalent cations) slows the rotation of the boundFl-AMP and leads to an increase in the fluorescence polarisation ratioof parallel to perpendicular light. Inhibition of the PDEreduces/inhibits this signal increase.

Test compounds (small volume, e.g. 0.5 to 1 ul, of solution in DMSO)were preincubated at ambient temperature (room temperature, e.g. 19-23°C.) in black 384-well microtitre plates (supplier: NUNC, code 262260)with PDE enzyme in 10 mM Tris-HCl buffer pH 7.2, 10 mM MgCl₂, 0.1% (w/v)bovine serum albumin, and 0.05% NaN₃ for 10-30 minutes. The enzyme levelwas set by experimentation so that reaction was linear throughout theincubation. Fluorescein adenosine 3′,5′-cyclic phosphate (from MolecularDevices Corporation, Molecular Devices code: R⁷⁰⁹¹) was added to giveabout 40 nM final concentration (final assay volume usually ca. 25-40ul). Plates were mixed on an orbital shaker for 10 seconds and incubatedat ambient temperature for 40 minutes. IMAP binding reagent (asdescribed above, from Molecular Devices Corporation, Molecular Devicescode: R⁷²⁰⁷) was added (60 ul of a 1 in 400 dilution in binding bufferof the kit stock solution) to terminate the assay. Plates were allowedto stand at ambient temperature for 1 hour. The FluorescencePolarisation (FP) ratio of parallel to perpendicular light was measuredusing an Analyst™ plate reader (from Molecular Devices Corporation). Forinhibition curves, 10 concentrations (1.5 nM-30 uM) of each compoundwere assayed. Curves were analysed using ActivityBase and XLfit (IDBusinesss Solutions Limited, 2 Ocean Court, Surrey Research Park,Guildford, Surrey GU2 7QB, United Kindgom). Results were expressed aspIC₅₀ values.

In the FP assay, all reagents were dispensed using Multidrop™ (availablefrom Thermo Labsystems Oy, Ratastie 2, PO Box 100, Vantaa 01620,Finland).

For a given PDE4 inhibitor, the PDE4B (or PDE4D) inhibition valuesmeasured using the SPA and FP assays can differ slightly. However, in aregression analysis of 100 test compounds, the pIC₅₀ inhibition valuesmeasured using SPA and FP assays have been found generally to agreewithin 0.5 log units, for PDE4B and PDE4D (linear regression coefficient0.966 for PDE4B and 0.971 for PDE4D; David R. Mobbs et al., “Comparisonof the IMAP Fluorescence Polarisation Assay with the ScintillationProximity Assay for Phosphodiesterase Activity”, poster to be presentedat 2003 Molecular Devices UK & Europe User Meeting, 2 Oct. 2003, DownHall, Harlow, Essex, United Kingdom).

Biological Data obtained for some of the Examples (PDE4B inhibitoryactivity, either as one reading or as an average of ca. 2-6 readings)are as follows, based on current measurements only. In each of the SPAand FP assays, absolute accuracy of measurement is not possible, and thereadings given are accurate only up to about ±0.5 of a log unit,depending on the number of readings made and averaged: PDE4B pIC₅₀Example number (± about 0.5) 2 8.0 3 7.8 6 6.6 11 7.4 21 8.5 22 7.9 327.7 40 8.3 63 6.9 1, 36, 39,41, 42, 43, 44, 47, 7.0 to 7.9 48, 63, 83,109, 178, 187 and 600 100, 155, 165, 167, 201, 8.2 to 10.0 260, 261,263, 265, 266, 267, 271, 431, 493, 494, 495, 498, 518, 518A, 528, 551,575, 581, 584, 619, 622, 624-626, 628, 630, 636, 638, 643-645, 653, and677 to 686 196 7.9 198 8.5

Examples 1-201 were generally tested for PDE4B inhibition using theradioactive SPA assay. Of Examples 207-665, and 677-686, all or almostall (except perhaps for Examples 451, 631-632, 635, 652) were tested forPDE4B inhibition; and of these some were tested by the radioactive SPAassay, some were tested by the FP assay. Examples 1-201, 207-450,452-630, 633-634, 636-651, 653-665, and 677-686, but excluding referenceexamples 19-20, have PDE4B inhibitory activities in the range ofpIC₅₀=about 6 (±about 0.5) to about 10.0 (±about 0.5). Examples 666-676are predicted to have PDE4B inhibitory activities in the range ofpIC₅₀=about 6 (±about 0.5) to about 10.0 (±about 0.5).

The Examples wherein R³=cyclohexyl (NHR³=sub-formula (c)),tetrahydro-2H-pyran-4-yl (NHR³=group (h)), 4-oxocyclohexyl(NHR³=sub-formula (o)), or certain other types of substituted cyclohexylor certain heterocycles, usually or often (especially with R¹=ethyl)have a higher level of selectivity for PDE4B over PDE5, as measured inthe above enzyme inhibition assays, compared to the selectivities ofcomparable Examples wherein R³=cyclopropyl (NHR³=sub-formula (b)). Forexample, based on current measurements only, and subject to cumulativeassay inaccuracies:

-   -   Examples 21, 41, 90, 198 and 201 (wherein NHR³=sub-formula (h),        (c), (j), (n) and (o) respectively, R¹=ethyl) have selectivities        for PDE4B over PDE5 in the range of about 3 to about 20 or more        times greater than the selectivity achieved for the equivalent        Example 39 wherein R³=cyclopropyl (NHR³=sub-formula (b));    -   Examples 43 and 44 (wherein NHR³=sub-formula (c) and (h)        respectively) have selectivities for PDE4B over PDE5 in the        range of about 4 to 8 or more times greater than the selectivity        achieved for the equivalent R³=cyclopropyl Example 42;    -   Examples 22 and 48 (wherein NHR³=sub-formula (h) and (c)        respectively) have selectivities for PDE4B over PDE5 in the        range of about 2.5 to 10 or more times greater than the        selectivity achieved for the equivalent R³=cyclopropyl Example        47; and    -   Examples 2 and 3 (wherein NHR³=sub-formula (c) and (h)        respectively) have selectivities for PDE4B over PDE5 in the        range of about 2 to 5 or more times greater than the selectivity        achieved for the equivalent R³=cyclopropyl Example 1.        Emesis: Some known PDE4 inhibitors can cause emesis and/or        nausea to greater or lesser extents (e.g. see Z. Huang et al.,        Current Opinion in Chemical Biology, 2001, 5: 432-438, see        especially pages 433-434 and refs cited therein). Therefore, it        would be preferable, but not essential, if a PDE4 inhibitory        compound or salt of the invention were to cause only limited or        manageable emetic side-effects. Emetic side-effects can for        example be measured by the emetogenic potential of the compound        or salt when administered to ferrets; for example one can        measure the time to onset, extent, frequency and/or duration of        vomiting, retching and/or writhing in ferrets after oral or        parenteral administration of the compound or salt. See for        example In vivo Assay 4 hereinafter for a measurement method for        anti-inflammatory effect, emetic side-effects and therapeutic        index (TI) in the ferret. See also for example A. Robichaud et        al., “Emesis induced by inhibitors of [PDE IV] in the ferret”,        Neuropharmacology, 1999, 38, 289-297, erratum Neuropharmacology,        2001, 40, 465-465. However, optionally, emetic side-effects and        therapeutic index (TI) in rats can be conveniently measured by        monitoring the pica feeding behaviour of rats after        administration of the compound or salt of the invention (see In        Vivo Assay 2 below).        Other side effects: Some known PDE4 inhibitors can cause other        side effects such as headache and other central nervous sytem        (CNS-) mediated side effects; and/or gastrointestinal (GI) tract        disturbances. Therefore, it would be preferable but not        essential if a particular PDE4 inhibitory compound or salt of        the invention were to cause only limited or manageable        side-effects in one or more of these side-effect categories.        In Vivo Biological Assays

The in vitro enzymatic PDE4B inhibition assay described above should beregarded as being the primary test of biological activity. However,additional in vivo biological tests, which are optional and which arenot an essential measure of efficacy or side-effects, are describedbelow.

In Vivo Assay 1. LPS-Induced Pulmonary Neutrophilia in Rats: Effect ofOrally Administered PDE4 Inhibitors

Pulmonary neutrophil influx has been shown to be a significant componentto the family of pulmonary diseases like chronic obstructive pulmonarydisease (COPD) which can involve chronic bronchitis and/or emphysema (G.F. Filley, Chest. 2000; 117(5); 251s-260s). The purpose of thisneutrophilia model is to study the potentially anti-inflammatory effectsin vivo of orally administered PDE4 inhibitors on neutrophilia inducedby inhalation of aerosolized lipopolysaccharide (LPS), modelling theneutrophil inflammatory component(s) of COPD. See the literature sectionbelow for scientific background.

Male Lewis rats (Charles River, Raleigh, N.C., USA) weighingapproximately 300-400 grams are pretreated with either (a) test compoundsuspended in 0.5% methylcellulose (obtainable from Sigma-Aldrich, StLouis, Mo., USA) in water or (b) vehicle only, delivered orally in adose volume of 10 ml/kg. Generally, dose response curves are generatedusing the following doses of PDE4 inhibitors: 10.0, 2.0, 0.4, 0.08 and0.016 mg/kg. Thirty minutes following pretreatment, the rats are exposedto aerosolized LPS (Serotype E. Coli 026:B6 prepared by trichloroaceticacid extraction, obtainable from Sigma-Aldrich, St Louis, Mo., USA),generated from a nebulizer containing a 100 μg/ml LPS solution. Rats areexposed to the LPS aerosol at a rate of 4 L/min for 20 minutes. LPSexposure is carried out in a closed chamber with internal dimensions of45 cm length×24 cm width×20 cm height. The nebulizer and exposurechamber are contained in a certified fume hood. At 4 hours-post LPSexposure the rats are euthanized by overdose with pentobarbital at 90mg/kg, administered intraperitoneally. Bronchoalveolar lavage (BAL) ispreformed through a 14 gauge blunt needle into the exposed trachea.Five, 5 ml washes are performed to collect a total of 25 ml of BALfluid. Total cell counts and leukocyte differentials are performed onBAL fluid in order to calculate neutrophil influx into the lung. Percentneutrophil inhibition at each dose (cf. vehicle) is calculated and avariable slope, sigmoidal dose-response curve is generated, usuallyusing Prism Graph-Pad. The dose-response curve is used to calculate anED50 value (in mg per kg of body weight) for inhibition by the PDE4inhibitor of the LPS-induced neutrophilia.

Results: Based on current measurements, the compounds of Examples 22, 83and 155, administered orally in the above procedure, exhibitedneutrophilia-inhibition ED50 values in the range of about 0.5 mg/kg toabout 2 mg/kg.

Alternative method and results: In an alternative embodiment of theprocedure, single oral doses of 10 mg/kg or 1.0 mg/kg of the PDE4inhibitor (or vehicle) is administered to the rats, and percentneutrophil inhibition is calculated and reported for that specific dose.In this embodiment, based on current measurements, the compounds ofExamples 21, 100, 109, 167, 172 and 600, administered orally in theabove procedure at a single dose of 1.0 mg/kg, exhibited percentneutrophilia-inhibition in the range of about 19% to about 69% (or inthe range of about 32% to about 69% for Examples 21, 100, 109, 167 and600).

LITERATURE

-   Filley G. F. Comparison of the structural and inflammatory features    of COPD and asthma. Chest. 2000; 117(5) 251s-260s.-   Howell R E, Jenkins L P, Fielding L E, and Grimes D. Inhibition of    antigen-induced pulmonary eosinophilia and neutrophilia by selective    inhibitors of phosphodiesterase types 3 and 4 in brown Norway rats.    Pulmonary Pharmacology. 1995; 8: 83-89.-   Spond J, Chapman R, Fine J, Jones H, Kreutner W, Kung T T,    Minnicozzi M. Comparison of PDE 4 inhibitors, Rolipram and SB 207499    (Ariflo™), in a rat model of pulmonary neutrophilia. Pulmonary    Pharmacology and Therapeutics. 2001; 14: 157-164.-   Underwood D C, Osborn RR, Bochnowicz S, Webb E F, Rieman D J, Lee J    C, Romanic A M, Adams J L, Hay D W P, and Griswold D E. SB 239063, a    p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines,    MMP-9, and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol.    2000; 279: L895-L902.    In Vivo Assay 2. Rat Pica Model of Emesis

Background: Selective PDE4 inhibitors have been shown to inhibitinflammation in various in vitro and in vivo models by increasingintracellular levels of cAMP of many immune cells (e.g. lymphocytes,monocytes). However, a side effect of some PDE4 inhibitors in manyspecies is emesis. Because many rat models of inflammation are wellcharacterized, they have been used in procedures (see e.g. In Vivo Assay1 above) to show beneficial anti-inflammatory effects of PDE 4inhibitors. However rats have no emetic response (they have no vomitreflex), so that the relationship between beneficial anti-inflammatoryeffects of PDE 4 inhibitors and emesis is difficult to study directly inrats.

However, in 1991, Takeda et al. (see Literature section below)demonstrated that the pica feeding response is analogous to emesis inrats. Pica feeding is a behavioural response to illness in rats whereinrats eat non-nutritive substances such as earth or in particular clay(e.g. kaolin) which may help to absorb toxins. Pica feeding can beinduced by motion and chemicals (especially chemicals which are emeticin humans), and can be inhibited pharmacologically with drugs thatinhibit emesis in humans. The Rat Pica Model, In Vivo Assay 2, candetermine the level of pica response of rats to PDE 4 inhibition atpharmacologically relevant doses in parallel to in vivoanti-inflammatory Assays in (a separate set of) rats (e.g. In Vivo Assay1 above). Anti-inflammatory and pica assays in the same species togethercan provide data on the “therapeutic index” (TI) in the rat of thecompounds/salts of the invention. The Rat TI can for example becalculated as the ratio of a) the potentially-emetic Pica Response ED50dose from Assay 2 to b) the rat anti-inflammatory ED50 dose (e.g.measured by rat neutrophilia-inhibition in eg In Vivo Assay 1), withlarger TI ratios possibly indicating lower emesis at manyanti-inflammatory doses. This might allow a choice of a non-emetic orminimal-emetic pharmaceutical dose of the compounds or salts of theinvention which has an anti-inflammatory effect. It is recognisedhowever that achieving a low-emetic PDE4 inhibitory compound is notessential.

Procedure: On the first day of the experiment, the rats are housedindividually in cages without bedding or “enrichment”. The rats are keptoff of the cage floor by a wire screen. Pre-weighed food cups containingstandard rat chow and clay pellets are placed in the cage. The claypellets, obtainable from Languna Clay Co, City of Industry, Calif., USA,are the same size and shape as the food pellets. The rats are acclimatedto the clay for 72 hours, during which time the cups and food and claydebris from the cage are weighed daily on an electronic balance capableof measuring to the nearest 0.1 grams. By the end of the 72 houracclimation period the rats generally show no interest in the claypellets.

At the end of 72 hours the rats are placed in clean cages and the foodcups weighed. Rats that are still consuming clay regularly are removedfrom the study. Immediately prior to the dark cycle (the time when theanimals are active and should be eating) the animals are split intotreatment groups and dosed orally with a dose of the compound/salt ofthe invention (different doses for different treatment groups) or withvehicle alone, at a dose volume of 2 ml/kg. In this oral dosing, thecompound/salt is in the form of a suspension in 0.5% methylcellulose(obtainable Sigma-Aldrich, St. Louis, Mo., USA) in water. The food andclay cups and cage debris are weighed the following day and the totalclay and food consumed that night by each individual animal iscalculated.

A dose response is calculated by first converting the data into quantalresponse, where animals are either positive or negative for the picaresponse. A rat is “pica positive” if it consumes greater than or equalto 0.3 grams of clay over the mean of is usually calculated usinglogistic regression performed by the Statistica software statisticalpackage. A Pica Response ED50 value in mg per kg of body weight can thenbe calculated.

Results: Using the above procedure, and according to currentmeasurements, the compounds of Examples 22, 83 and 155 exhibited a PicaResponse ED50 in the range of about 4.8 mg/kg to greater than or equalto about 40 mg/kg. It can be seen that these Pica Response ED50 dosesare higher than the neutrophilia-inhibition ED50 values for these threeExamples (see In Vivo Assay 1 above), so that a Therapeutic Index (TI)in rats of >2, as measured by Assays 1+2 and according to currentmeasurements, appears at first sight to have been achieved for thesethree Examples.

The Therapeutic Index (TI) calculated this way is often significantlydifferent to, and often higher than, the TI calculated in the ferret(see In vivo Assay 4 below).

LITERATURE

-   Beavo J A, Contini, M., Heaslip, R. J. Multiple cyclic nucleotide    phosphodiesterases. Mol Pharmacol. 1994; 46:399-405.-   Spond J, Chapman R, Fine J, Jones H, Kreutner W, Kung TT,    Minnicozzi M. Comparison of PDE 4 inhibitors, Rolipram and SB 207499    (Ariflo™), in a rat model of pulmonary neutrophilia. Pulmonary    Pharmacology and Therapeudtics. 2001; 14:157-164.-   Takeda N, Hasegawa S, Morita M, and Matsunaga T. Pica in rats is    analogous to emesis: an animal model in emesis research.    Pharmacology, Biochemistry and Behavior. 1991; 45:817-821.-   Takeda N, Hasegawa S, Morita M, Horii A, Uno A, Yamatodani A and    Matsunaga T. Neuropharmacological mechanisms of emesis. I. Effects    of antiemetic drugs on motion- and apomorphine-induced pica in rats.    Meth Find Exp Clin Pharmacol. 1995; 17(9) 589-596.-   Takeda N, Hasegawa S, Morita M, Horii A, Uno A, Yamatodani A and    Matsunaga T. Neuropharmacological mechanisms of emesis. II. Effects    of antiemetic drugs on cisplatin-induced pica in rats. Meth Find Exp    Clin Pharmacol. 1995; 17(9) 647-652.    In Vivo Assay 3. LPS Induced Pulmonary Neutrophilia in Rats: Effect    of Intratracheally Administered PDE4 Inhibitors

This assay is an animal model of inflammation in the lung—specificallyneutrophilia induced by lipopolysaccharide (LPS)—and allows the study ofputative inhibition of such neutrophilia (anti-inflammatory effect) byintratracheally (i.t.) administered PDE4 inhibitors. The PDE4 inhibitorsare preferably in dry powder or wet suspension form. I.t. administrationis one model of inhaled administration, allowing topical delivery to thelung.

Animals: Male CD (Sprague Dawley Derived) rats supplied by CharlesRiver, Raleigh, N.C., USA were housed in groups of 5 rats per cage,acclimatised after delivery for at least 7 days with bedding/nestingmaterial regularly changed, fed on SDS diet R¹ pelleted food given adlib, and supplied with daily-changed pasteurised animal grade drinkingwater.

Device for dry powder administration: Disposable 3-way tap betweendosing needle and syringe. A 3-way sterile tap (Vycon Ref 876.00) wasweighed, the drug blend or inhalation grade lactose (vehicle control)was then added to the tap, the tap closed to prevent loss of drug, andthe tap was re-weighed to determine the weight of drug in the tap. Afterdosing, the tap was weighed again to determine the weight of drug thathad left the tap. The needle, a Sigma Z21934-7 syringe needle 19-gauge152 mm (6 inches) long with luer hub, was cut by engineering toapproximately 132 mm (5.2 inches), a blunt end was made to prevent themdamaging the rat's trachea, and the needle weighed prior to and afterdrug delivery to confirm that no drug was retained in the needles afterdosing.

Device for wet suspension administration: This is the similar to theabove but a blunt dosing needle, whose forward end was slightly angledto the needle axis, was used, with a flexible plastic portex canulainserted into the needle.

Drugs and Materials: Lipopolysaccharide (LPS) (Serotype:0127:B8) (L3129Lot 61K4075) was dissolved in phosphate-buffered saline (PBS). PDE4inhibitors are used in size-reduced (e.g. micronised) form, for exampleaccording to the Micronisation Example given above. For dry powderadministration of the drug, the Dry Powder Formulation Example givenabove, comprising drug and inhalation-grade lactose, can be used. Theinhalation-grade lactose usually used (Lot E98L4675 Batch 845120) has10% fines (10% of material under 15 um particle size measured by Malvernparticle size).

Wet suspensions of the drug can be prepared by adding the requiredvolume of vehicle to the drug; the vehicle used being a mixture ofsaline/tween (0.2% tween 80). The wet suspension was sonicated for 10minutes prior to use.

Preparation, and dosing with PDE 4 inhibitor: Rats were anaesthetised byplacing the animals in a sealed Perspex chamber and exposing them to agaseous mixture of isoflourane (4.5%), nitrous oxide (3 litres.minute⁻¹)and oxygen (1 litre.minute⁻¹). Once anaesthetised, the animals wereplaced onto a stainless steel i.t. dosing support table. They werepositioned on their back at approximately a 35° angle. A light wasangled against the outside of the throat to highlight the trachea. Themouth was opened and the opening of the upper airway visualised. Theprocedure varies for wet suspension and dry powder administration ofPDE4 inhibitors as follows:

Dosing with a Wet suspension: A portex cannula was introduced via ablunt metal dosing needle that had been carefully inserted into the rattrachea. The animals were intratracheally dosed with vehicle or PDE4inhibitor via the dosing needle with a new internal canula used for eachdifferent drug group. The formulation was slowly (10 seconds) dosed intothe trachea using a syringe attached to the dosing needle.

Dosing with a Dry Powder: The three-way tap device and needle wereinserted into the rat trachea up to a pre-determined point establishedto be located approximately 1 cm above the primary bifurcation. Anotheroperator holds the needle at the specified position whilst 2×4 ml of airis delivered through the three-way tap by depressing the syringes(ideally coinciding with the animal inspiring), aiming to expel theentire drug quantity from the tap. After dosing, the needle and tap areremoved from the airway and the tap closed off to prevent any retaineddrug leaving the tap. After dosing with either wet suspension or drypowder, the animals are then removed from the table and observedconstantly until they have recovered from the effects of anaesthesia.The animals are returned to the holding cages and given free access tofood and water; they are observed and any unusual behavioural changesnoted.

Exposure to LPS: About 2 hours after i.t. dosing with vehicle control orthe PDE4 inhibitor, the rats were placed into sealed Perspex containersand exposed to an aerosol of LPS (nebuliser concentration 150 μg.ml⁻¹)for 15 minutes. Aerosols of LPS were generated by a nebuliser(DeVilbiss, USA) and this was directed into the Perspex exposurechamber. Following the 15-minute LPS-exposure period, the animals werereturned to the holding cages and allowed free access to both food andwater.

[In an alternative embodiment, the rats can exposed to LPS less than 2hours after i.t. dosing. In another alternative embodiment, the rats canexposed to LPS more than 2 hours (e.g. ca. 4 or ca. 6 hours) after i.t.dosing by vehicle or PDE4 inhibitor, to test whether or not the PDE4inhibitor has a long duration of action (which is not essential).]

Bronchoalveolar ravage: 4 hours after LPS exposure the animals werekilled by overdose of sodium pentobarbitone (i.p.). The trachea wascannulated with polypropylene tubing and the lungs lavaged (washed out)with 3×5 mls of heparinised (25 units.ml⁻¹) phosphate buffered saline(PBS).

Neutrophil cell counts: The Bronchoalveolar lavage (BAL) samples werecentrifuged at 1300 rpm for 7 minutes. The supernatant was removed andthe resulting cell pellet resuspended in 1 ml PBS. A cell slide of theresuspension fluid was prepared by placing 100 μl of resuspended BALfluid into cytospin holders and then spun at 5000 rpm for 5 minutes. Theslides were allowed to air dry and then stained with Leishmans stain (20minutes) to allow differential cell counting. The total cells were alsocounted from the resuspension. From these two counts, the total numbersof neutrophils in the BAL were determined. For a measure ofPDE4-inhibitor-induced inhibition of neutrophilia, a comparison of theneutrophil count in rats treated with vehicle and rats treated with PDE4inhibitors is conducted.

By varying the dose of the PDE4 inhibitor used in the dosing step (e.g.0.2 or 0.1 mg of PDE4 inhibitor per kg of body weight, down to e.g. 0.01mg/kg), a dose-response curve can be generated.

In Vivo Assay 4. Evaluation of Therapeutic Index of PDE 4 Inhibitors inthe Conscious Ferret

1.1 Materials

The following materials are used for these studies:

PDE4 inhibitors are prepared for oral (p.o.) administration bydissolving in a fixed volume (1 ml) of acetone and then adding cremophorto 20% of the final volume. Acetone is evaporated by directing a flow ofnitrogen gas onto the solution. Once the acetone is removed, thesolution is made up to final volume with distilled water. LPS isdissolved in phosphate buffered saline.

1.2 Animals

Male ferrets (Mustela Pulorius Furo, weighing 1-2 kg) are transportedand allowed to acclimatise for not less than 7 days. The diet comprisesSDS diet C pelleted food given ad lib with Whiskers™ cat food given 3times per week. The animals are supplied with pasteurised animal gradedrinking water changed daily.

1.3 Experimental Protocol(s)

1.3.1 Dosing with PDE4 Inhibitors

PDE4 inhibitors are administered orally (p.o.), using a dose volume of 1ml/kg. Ferrets are fasted overnight but allowed free access to water.The animals are orally dosed with vehicle or PDE 4 inhibitor using a 15cm dosing needle that is passed down the back of the throat into theoesophagus. After dosing, the animals are returned to holding cagesfitted with perspex doors to allow observation, and given free access towater. The animals are constantly observed and any emetic episodes(retching and vomiting) or behavioural changes are recorded. The animalsare allowed access to food 60-90 minutes after p.o. dosing.

1.3.2 Exposure to LPS

Thirty minutes after oral dosing with compound or vehicle control, theferrets are placed into sealed perspex containers and exposed to anaerosol of LPS (30 μg/ml) for 10 minutes. Aerosols of LPS are generatedby a nebuliser (DeVilbiss, USA) and this is directed into the perspexexposure chamber. Following a 10-minute exposure period, the animals arereturned to the holding cages and allowed free access to water, and at alater stage, food. General observation of the animals continues for aperiod of at least 2.5 hours post oral dosing. All emetic episodes andbehavioural changes are recorded.

1.3.3 Bronchoalveolar Lavage and Cell Counts

Six hours after LPS exposure the animals are killed by overdose ofsodium pentobarbitone administered intraperitoneally. The trachea isthen cannulated with polypropylene tubing and the lungs lavaged twicewith 20 ml heparinised (10 units/ml) phosphate buffered saline (PBS).The bronchoalveolar lavage (BAL) samples are centrifuged at 1300 rpm for7 minutes. The supernatant is removed and the resulting cell pelletre-suspended in 1 ml PBS. A cell smear of re-suspended fluid is preparedand stained with Leishmans stain to allow differential cell counting. Atotal cell count is made using the remaining re-suspended sample. Fromthis, the total number of neutrophils in the BAL sample is determined.

1.3.4 Pharmacodynamic Readouts

The following parameters are recorded:

-   a) % inhibition of LPS-induced pulmonary neutrophilia to determine    the dose of PDE4 inhibitor which gives 50% inhibition (D50).-   b) Emetic episodes—the number of vomits and retches are counted to    determine the dose of PDE4 inhibitor that gives a 20% incidence of    emesis (D20).-   c) A therapeutic index (TI), using this assay, is then calculated    for each PDE4 inhibitor using the following equation:    ${{Therapeutic}\quad{index}\quad({TI})} = \frac{{D20}\quad{incidence}\quad{of}\quad{emesis}}{{D50}\quad{inhibition}\quad{of}\quad{neutrophilia}}$

It is noted that the Therapeutic index (TI) calculated using this invivo Assay 4 is often significantly different to, and often lower than,that calculated using the rat oral inflammation and pica feeding Assays1+2.

The calculation of TI using the PDE4 inhibitor roflumilast in this Assay4 is:

-   D20 for emesis=0.5 mg/kg p.o., D50 for neutroplilia=0.49 mg/kg p.o.,    T_(RET)=1.02

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

EXAMPLES

The various aspects of the invention will now be described by referenceto the following examples. These examples are merely illustrative andare not to be construed as a limitation of the scope of the presentinvention. In this section, “Intermediates” represent syntheses ofintermediate compounds intended for use in the synthesis of the“Examples”.

Abbreviations used herein: DMSO dimethyl sulfoxide DCM dichloromethaneEtOAc ethyl acetate Et₂O diethyl ether DMF dimethyl formamide MeOHmethanol HPLC high pressure liquid chromatography SPE solid phaseextraction NMR nuclear magnetic resonance (in which: s = singlet, d =doublet, t = triplet, q = quartet, dd = doublet of doublets, m =multiplet, H = no. of protons) LCMS liquid chromatography/massspectroscopy TLC thin layer chromatography BEMP2-t-butylimino-2-diethylamino-1,3- dimethylperhydro-1,3,2-diazaphosphazine EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HBTUO-(Benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphateHOBT hydroxybenzotriazole = 1-hydroxybenzotriazole h hours DIPEAdiisopropylethyl amine (^(i)Pr₂NEt) ^(T)RET retention time THFTetrahydrofuran Lawesson's2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4- reagentdisuiphide Room this is usually in the range of about 20 to about 25° C.temperatureMachine Methods Used Herein:

-   LCMS (liquid chromatography/mass spectroscopy)-   Waters ZQ mass spectrometer operating in positive ion electrospray    mode, mass range-   100-1000 amu.-   UV wavelength: 215-330 nM-   Column: 3.3 cm×4.6 mm ID, 3 μm ABZ+PLUS-   Flow Rate: 3 ml/min-   Injection Volume: 5 μl-   Solvent A: 95% acetonitrile+0.05% formic acid-   Solvent B: 0.1% formic acid+10 mMolar ammonium acetate-   Gradient: 0% A/0.7 min, 0-100% A/3.5 min, 100% A/1.1 min, 100-0%    A/0.2 min    Mass Directed Autoprep HPLC

The prep column used was a Supelcosil ABZplus (10 cm×2.12 cm) (usually10 cm×2.12 cm×5 μm).

-   UV wavelength: 200-320 nM-   Flow: 20 ml/min-   Injection Volume: 1 ml; or more preferably 0.5 ml-   Solvent A: 0.1% formic acid-   Solvent B: 95% acetonitrile+5% formic acid; or more usually 99.95%    acetonitrile+0.05% formic acid-   Gradient: 100% A/1 min, 100-80% A/9 min, 80-1% A/3.5 min, 1% A/1.4    min, 1-100% A/0.1 min

INTERMEDIATES AND EXAMPLES

All reagents not detailed in the text below are commercially availablefrom established suppliers such as Sigma-Aldrich. The addresses of thesuppliers for some of the starting materials mentioned in theIntermediates and Examples below or the Assays above are as follows:

-   ABCR GmbH & CO. KG, P.O. Box 21 01 35, 76151 Karlsruhe, Germany-   Aceto Color Intermediates (catalogue name), Aceto Corporation, One    Hollow Lane, Lake Success, N.Y., 11042-1215, USA-   Acros Organics, A Division of Fisher Scientific Company, 500    American Road, Morris Plains, N.J. 07950, USA-   Apin Chemicals Ltd., 82 C Milton Park, Abingdon, Oxon OX14 4RY,    United Kingdom-   Apollo Scientific Ltd., Unit 1A, Bingswood Industrial Estate, Whaley    Bridge, Derbyshire SK23 7LY, United Kingdom-   Aldrich (catalogue name), Sigma-Aldrich Company Ltd., Dorset, United    Kingdom, telephone: +44 1202 733114; Fax: +44 1202 715460;    ukcustsvieumotes.sial.com; or-   Aldrich (catalogue name), Sigma-Aldrich Corp., P.O. Box 14508, St.    Louis, Mo. 63178-9916, USA; telephone: 314-771-5765; fax:    314-771-5757; custservsial.com; or-   Aldrich (catalogue name), Sigma-Aldrich Chemie Gmbh, Munich,    Germany; telephone: +49 89 6513 0; Fax: +49 89 6513 1169;    deordersteurnotes.sial.com.-   Alfa Aesar, A Johnson Matthey Company, 30 Bond Street, Ward Hill,    Mass. 01835-8099, USA-   Amersham Biosciences UK Ltd, Pollards Wood, Chalfont St Giles,    Buclinghamshire HP8 4SP, United Kingdom-   Array Biopharma Inc., 1885 33rd Street, Boulder, Colo. 80301, USA-   AstaTech, Inc., 8301 Torresdale Ave., 19C, Philadelphia, Pa. 19136,    USA-   Austin Chemical Company, Inc., 1565 Barclay Blvd., Buffalo Grove,    Ill. 60089, USA-   Avocado Research, Shore Road, Port of Heysham Industrial Park,    Heysham Lancashire LA3 2XY, United Kingdom-   Bayer AG, Business Group Basic and Fine Chemicals, D-51368    Leverkusen, Germany-   Berk Univar plc, Berk House, P.O. Box 56, Basing View, Basingstoke,    Hants RG21 2E6, United Kingdom-   Butt Park Ltd., Braysdown Works, Peasedown St. John, Bath BA2 8LL,    United Kingdom-   Chemical Building Blocks (catalogue name), Ambinter, 46 quai Louis    Bleriot, Paris, F-75016, France-   ChemBridge Europe, 4 Clark's Hill Rise, Hampton Wood, Evesham,    Worcestershire WR11 6FW, United Kingdom-   ChemService Inc., P.O. Box 3108, West Chester, Pa. 19381, USA-   Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San Diego,    Calif. 92126, USA-   Dynamit Nobel GmbH, Germany; also available from: Saville Whittle    Ltd (UK agents of Dynamit Nobel), Vickers Street, Manchester M40    8EF, United Kingdom-   E. Merck, Germany; or E. Merck (Merck Ltd), Hunter Boulevard, Magna    Park, Lutterworth, Leicestershire LE17 4XN, United Kingdom-   Esprit Chemical Company, Esprit Plaza, 7680 Matoaka Road, Sarasota,    Fla. 34243, USA-   Exploratory Library (catalogue name), Ambinter, 46 quai Louis    Bleriot, Paris, F-75016, France-   Fluka Chemie AG, Industriestrasse 25, P.O. 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Ultrafine (UFC Ltd.), Synergy House, Guildhall Close, Manchester SciencePark, Manchester M15 6SY, United Kingdom Table of Intermediates Inter-mediate Number Name 1 Ethyl4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 2 Ethyl4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 3 Ethyl1-methyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 4 Ethyl1-benzyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 5 Ethyl4-chloro-l-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 61-Acetyl-4-aminopiperidine 7 1-Methyl-4-aminopiperidine 84-Aminotetrahydropyran 8A Tetrahydro-2H-pyran-4-amine hydrochloride =4-Aminotetrahydropyran hydrochloride 9 (R)-(+)-3-Amino tetrahydrofuran4-toluene sulphonate 10 (S)-(−)-3-Amino tetrahydrofuran 4-toluenesulphonate 11 Tetrahydro-2H-thiopyran-4-amine 12Tetrahydro-3-thiopheneamine 13 Tetrahydro-3-thiopheneamine 1,1-dioxidehydrochloride 14 Tetrahydro-2H-thiopyran-4-amine-1,1-dioxidehydrochloride 154-Chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 164-Cbloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl chloride 17N-Benzyl-4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 184-Chloro-1-ethyl-N-(2-ethylbutyl)-1H-pyrazolo[3,4-]pyridine-5-carboxaxnide194-Chloro-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide204-Chloro-N-cyclopentyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide214-Chloro-1-ethyl-5-(pyrrolidin-1-ylcarbonyl)-1H-pyrazolo[3,4-b]pyridine22 4-Chloro-1-ethyl-N-,yridin-4-ylmethyl)-1H-pyrazolo[3,4-]pyridine-5-carboxamide 234-Chloro-1-ethyl-N-propyl-1H-pyrazololl3,4-b]pyridine-5-carboxamide 244-Chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 25 Ethyl4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 264-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 274-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl chloride 28N-Benzyl-4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 294-Chloro-1-methyl-N-4-fluorophenyl-1H-pyrazolo[3,4]pyridine-5-carboxamide304-Chloro-1-methyl-N-(2-ethylbutyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide31 4-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 32 Ethyl1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 331-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 34 Ethyl1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 35 Ethyl1-ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 36 Ethyl1-ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 37 Ethyl1-ethyl-4-(tetrahydrothien-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 38 Ethyl4-(cyclopropylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 39Ethyl4-[(1,1-dioxidotetrahyclrothien-3-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 40 Ethyl4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 411-Ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 42 Ethyl1-ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 431-Ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 441-Ethyl-4-(tetrahydrothien-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic45 4-(Cyclopropylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid 464-[(1,1-Dioxidotetrahydrothien-3-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 474-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 48 Ethyl4-(cyclohexylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 494-(Cyclohexylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 501-n-Propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 51 Ethyl4-chloro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 524-(Cyclohexylamino)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid 531-Ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 54 4-Aminocyclohexanone hydrochloride 761-Ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

Intermediate 1: Ethyl4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Prepared from commercially available 5-amino-1-ethyl pyrazole asdescribed by G. Yu et al. in J. Med. Chem., 2001, 44, 1025-1027:

Intermediate 2: Ethyl 4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Can be prepared by oxidative cleavage (SeO₂) of 1-furanylmethylderivative, as described by T. M. Bare et. al. In J. Med. Chem., 1989,32, 2561-2573, (further ed to Zuleski, F. R., Kirkland, K. R., Melgar,M. D.; Malbica, J. Drug. Metab. Dispos. 1985, 13, 139)

Intermediate 3: Ethyl1-methyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of Intermediate 2 (0.47 g) and anhydrous potassium carbonate(0.83 g) (previously dried by heating at 100° C.) in anhydrousdimethylformamide (DMF) (4 ml) was treated with iodomethane (0.26 ml)and stirred vigorously for 3 h. The mixture was then filtered and thefiltrate concentrated in vacuo to afford a residual oil, which waspartitioned between dichloromethane (DCM) (25 ml) and water (25 ml). Thelayers were separated and the aqueous phase was extracted with furtherDCM (2×25 ml). The combined organic extracts were dried over anhydroussodium sulphate and evaporated to an orange solid which was applied toan SPE cartridge (silica, 20 g). The cartridge was eluted sequentiallywith EtOAc:petrol (1:4, 1:2 and 1:1), then chloroform:methanol (49:1,19:1 and 9:1). Fractions containing desired material were combined andconcentrated in vacuo to afford Intermediate 3 (0.165 g). LCMS showedMH⁺=250; T_(RET)=2.59 min.

Intermediate 4: Ethyl1-benzyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of Intermediate 2 (0.47 g) and anhydrous potassium carbonate(0.83 g) (previously dried by heating at 100° C.) in anhydrous DMF (4ml) was treated with benzyl bromide (0.72 g) then stirred vigorously andheated at 55° C. for 4.5 h. The mixture was allowed to cool, thenfiltered and the filtrate concentrated in vacuo to afford a residualoil, which was partitioned between DCM (25 ml) and water (25 ml). Thelayers were separated and the aqueous phase was extracted with furtherDCM (2×25 ml). The combined organic extracts were dried over anhydroussodium sulphate and evaporated to a yellow oily solid which wasdissolved in DCM and applied to an SPE cartridge (silica, 20 g). Thecartridge was eluted with a gradient of EtOAc:petrol (1:4, 1:2 and 1:1)then chloroform:methanol (49:1, 19:1 and 9:1). Fractions containingdesired material were combined and concentrated in vacuo to affordIntermediate 4 (0.33 g). LCMS showed MH⁺=326; T_(RET)=3.24 min.

Intermediate 5: Ethyl4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of 5-amino-1-phenyl pyrazole (2.0 g) anddiethylethoxymethylene malonate (2.54 ml) was heated under Dean Starkconditions at 120° C. for 16 h. The solution was cooled, phosphorusoxychloride (16 ml) was then added and the mixture heated under refluxfor a further 20 h. Excess phosphorus oxychloride was removed in vacuoand the residue partitioned between diethyl ether and water, proceedingwith extreme caution on addition of water. The ethereal layer was washedwith further water, then dried over magnesium sulphate and concentratedin vacuo to afford ethyl4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (2.09 g).LCMS showed MH⁺=302; T_(RET)=3.80 min.

Intermediate 6: 1-Acetyl-4-aminopiperidine

Prepared from commercially available N1-benzyl-4-aminopiperidine asdescribed by Yamada et. al. In WO 00/42011:

Intermediate 7: 1-Methyl-4-aminopiperidine

Prepared from commercially available N-methyl-4-piperidone as describedby C. M. Andersson et. al. in WO01/66521:

Intermediate 8: 4-Aminotetrahydropyran

Commercially available from Combi-Blocks Inc., 7949 Silverton Avenue,Suite 915, San Diego, Calif. 92126, USA (CAS 38041-19-9)

Intermediate 8A: Tetrahydro-2H-pyran-4-aminehydrochloride=4-Aminotetrahydropyran hydrochloride

Step 1: N,N-dibenzyltetrahydro-2H-pyran-4-amine

Dibenzylamine (34.5 g) and acetic acid (6.7 ml) were added to a stirredsolution of tetrahydro-4H-pyran-4-one (16.4 g, commercially availablefrom e.g. Aldrich) in dichloromethane (260 ml) at 0° C. to 5° C. After2.5 h at 0° C. to 5° C., sodium triacetoxyborohydride (38.9 g) was addedportionwise, and the mixture was allowed to warm to room temperature.After stirring at room temperature overnight, the reaction mixture waswashed successively with 2M-sodium hydroxide (200 ml and 50 ml), water(2×50 ml) and brine (50 ml), then dried and evaporated to give a yellowoil (45 g). This oil was stirred with methanol (50 ml) at 4° C. for 30min to give the product as a white solid (21.5 g). LCMS showed MH⁺=282;T_(RET)=1.98 min.

Step 2: Tetrahydro-2H-pyran-4-amine hydrochloride

N,N-dibenzyltetrahydro-2H-pyran-4-amine (20.5 g) was dissolved inethanol (210 ml) and hydrogenated over 10% palladium on carbon catalyst(4 g) at 100 psi for 72 h at room temperature. The reaction mixture wasfiltered and the filtrate was adjusted to pH 1 with 2M-hydrogen chloridein diethyl ether. Evaporation of solvents gave a solid which wastriturated with diethyl ether to give the product as a white solid (9.23g). ¹H NMR (400 MHz in dr-DMSO, 27° C., δppm) 8.24 (br. s, 3H), 3.86(dd, 12, 4 Hz, 2H), 3.31 (dt, 2, 12 Hz, 2H), 3.20 (m, 1H), 1.84 (m, 2H),1.55 (dq, 4, 12 Hz, 2H).

Intermediate 9: (R)-(+)-3-Amino tetrahydrofuran 4-toluenesulphonate

Commercially available from Fluka Chemie AG, Germany (CAS 111769-27-8)

Intermediate 10: (S)-(−)-3-Amino tetrahydrofuran 4-toluenesulphonate

Commercially available from E. Merck, Germany; or from E. Merck (MerckLtd), Hunter Boulevard, Magna Park Lutterworth, Leicestershire LE17 4XN,United Kingdom (CAS 104530-80-5)

Intermediate 11: Tetrahydro-2H-thiopyran-4-amine

Prepared from commercially available tetrahydrothiopyran-4-one asdescribed by Subramanian et. al., J. Org. Chem., 1981, 46, 4376-4383.Subsequent preparation of the hydrochloride salt can be achieved byconventional means.

Intermediate 12: Tetrahydro-3-thiopheneamine

Prepared in an analogous manner to Intermediate 11 from commerciallyavailable tetrahydrothiophene-4-one. The oxime formation is described byGrigg et.al., Tetrahedron, 1991, 47, 4477-4494 and the oxime reductionby Unterhalt et. al., Arch. Pharm., 1990, 317-318.

Intermediate 13: Tetrahydro-3-thiopheneamine 1,1-dioxide hydrochloride

Commercially available from Sigma Aldrich Library of Rare Chemicals(SALOR) (CAS-6338-70-1). Preparation of the hydrochloride salt of theamine can be achieved by conventional means.

Intermediate 14: Tetrahydro-2H-thiopyran-4-amine-1,1-dioxidehydrochloride

Prepared in an analogous manner to Intermediate 11 from commerciallyavailable tetrahydrothiophene-4-one. Oxidation to1,1-dioxo-tetrahydro-1λ⁶-thiopyran-4-one is described by Rule et. al.,in J. Org. Chem., 1995, 60, 1665-1673. Oxime formation is described byTruce et.al., in J. Org. Chem., 1957, 617, 620 and oxime reduction byBarkenbus et. al., J. Am. Chem. Soc., 1955, 77, 3866. Subsequentpreparation of the hydrochloride salt of the amine can be achieved byconventional means.

Intermediate 15:4-Chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

A solution of Intermediate 1 (3.5 g) in dioxane (28 ml) was treated withpotassium hydroxide (6.3 g) as a solution in water (20 ml). The mixturewas stirred for 2 h, then concentrated in vacuo, acidified to pH 3 with2M aqueous hydrochloric acid and extracted with ethyl acetate. Thelayers were separated, the organic layer dried over sodium sulphate,then concentrated in vacuo to afford Intermediate 15 as a white solid(2.4 g). LCMS showed MH⁺=226; T_(RET)=2.62 min.

Intermediate 17:N-Benzyl-4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

That is, Intermediate 17 is:

Intermediate 15 (3.5 g) was dried over phosphorus pentoxide for 1 h,then treated with thionyl chloride (47 g). The mixture was stirred andheated at 75° C. for 1.3 h. Excess thionyl chloride was removed in vacuoand the residual oil azeotroped with dichloromethane (DCM) to affordIntermediate 16, presumed to be the acid chloride derivative ofIntermediate 15, as a white solid (3.3 g).

Intermediate 16 (0.473 g) was dissolved in tetrahydrofuran (TBF) (4 ml)and treated with N,N-diisopropylethylamine (DIPEA) (0.509 ml), then withbenzylamine (0.209 g) and the mixture stirred under nitrogen for 0.5 h.The mixture was concentrated in vacuo, then partitioned betweendichloromethane and water. The layers were separated and the organicsconcentrated in vacuo to afford Intermediate 17 (0.574 g). LCMS showedMH⁺=315; T_(RET)=2.90 min.

Similarly prepared were the following:

Amine MH⁺ NR⁴R⁵ reagent ion T_(RET) (min) Intermediate 18

2-Ethyl-N- butylamine 309 3.07 Intermediate 19

4-Fluoro- aniline 319 3.08 Intermediate 20

Cyclo- pentylamine 293 2.76 Intermediate 21

Pyrrolidine 279 2.46

Intermediate 22:4-Chloro-1-ethyl-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Acid chloride Intermediate 16 was synthesised from Intermediate 15 usingthe method shown above for Intermediate 17. Intermediate 16 (0.473 g)was dissolved in THF (4 ml) and treated with diisopropylethylamine(DIPEA) (0.509 ml), then with 4-(aminomethyl)pyridine (0.211 g) and themixture stirred under nitrogen for 0.5 h. The mixture was concentratedin vacuo, then partitioned between DCM and water. The layers wereseparated and the organics concentrated in vacuo, then applied to an SPEcartridge (silica, 10 g) which was eluted with a gradient ofcyclohexane:EtOAc (2:1 increasing stepwise up to 0:1), followed byMeOH:EtOAc (5:95, then 10:90). Fractions containing desired materialwere combined and concentrated in vacuo to afford Intermediate 22 (0.086g). LCMS showed MH⁺=316; T_(RET)=1.84 min.

Intermediate 23:4-Chloro-1-ethyl-N-n-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Acid chloride Intermediate 16 was synthesised from Intermediate 15 usingthe method shown above for Intermediate 17. Intermediate 16 (0.473 g)was dissolved in TBF (4 ml) and treated with DIPEA (0.509 ml), then withn-propyl amine (0.115 g) and the mixture stirred under nitrogen for 0.5h. A further portion of n-propyl amine (0.023 g) was then added andstirring continued for 18 h. The mixture was concentrated in vacuo, thenpartitioned between DCM and water. The layers were separated and theorganics concentrated in vacuo to afford Intermediate 23 (0.405 g). LCMSshowed MH⁺=267; T_(RET)=2.54 min.

Intermediate 24:4-Chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Acid chloride Intermediate 16 was synthesised from Intermediate 15 usingthe method shown above for Intermediate 17. Intermediate 16 (0.30 g) wasdissolved in THF (3 ml) and treated with a 0.5M solution of ammonia indioxane (4.92 ml). The mixture was stirred under nitrogen for 18 h. Afurther portion of 0.5M ammonia in dioxane (4.92 ml) was added andstirring continued for 72 h. The mixture was concentrated in vacuo andthe residue partitioned between DCM and 2M sodium hydroxide solution.The layers were separated and the organics concentrated to affordIntermediate 24 (0.278 g). LCMS showed MH⁺=225; T_(RET)=2.10 min.

Intermediate 25: Ethyl4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of 5-amino-1-methylpyrazole (4.0 g) and diethylethoxymethylenemalonate (9.16 ml) was heated at 150° C. under Dean Stark conditions for5 h. Phosphorous oxychloride (55 ml) was carefully added to the mixtureand the resulting solution heated at 130° C. under reflux for 18 h. Themixture was concentrated in vacuo, then the residual oil cooled in anice bath and treated carefully with water (100 ml)(caution: exotherm).The resulting mixture was extracted with DCM (3×100 ml) and the combinedorganic extracts were dried over anhydrous sodium sulphate andconcentrated in vacuo. The residual solid was purified by Biotagechromatography (silica, 90 g), eluting with Et₂O:petrol (1:3). Fractionscontaining desired material were combined and concentrated in vacuo toafford Intermediate 25 (4.82 g). LCMS showed MH⁺=240; T_(RET)=2.98 min

Intermediate 26:4-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

A solution of Intermediate 25 (4.0 g) in dioxane (30 ml) was treatedwith potassium hydroxide (7.54 g) as a solution in water (20 ml). Themixture was stirred for 16 h, then diluted with water (150 ml) andacidified to pH 3 with 5M aqueous hydrochloric acid. The mixture wasstirred in an ice bath for 15 min, then collected by filtration, washedwith ice-cold water and dried in vacuo over phosphorous pentoxide toafford Intermediate 26 as a white solid (2.83 g). LCMS showed MH⁺=212;T_(RET)=2.26 min.

Intermediate 28:N-Benzyl-4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Intermediate 26 (2.5 g) (previously dried over phosphorus pentoxide) wastreated with thionyl chloride (25 ml) and the mixture heated underreflux for 1 h. Excess thionyl chloride was removed in vacuo to affordIntermediate 27, presumed to be the acid chloride derivative ofIntermediate 26, as a white solid (2.7 g).

Intermediate 27 (0.68 g) was dissolved in THF (10 ml) and treated withDIPEA (0.77 ml), then with benzyl amine (0.339 g) and the mixturestirred under nitrogen for 3 h. The mixture was concentrated in vacuo,then partitioned between DCM (20 ml) and water (10 ml). The layers wereseparated and the organics concentrated in vacuo to afford Intermediate28 (0.90 g). LCMS showed MH⁺=301; T_(RET)=2.72 min.

Similarly prepared were the following:

Amine MH⁺ NR⁴R⁵ reagent ion T_(RET) (min) Intermediate 29

4-Fluoro- aniline 305 2.91 Intermediate 19

2-Ethyl-N- butylamine 295 2.97

Intermediate 31:4-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Acid chloride Intermediate 27 was synthesised from Intermediate 26 usingthe method shown above for Intermediate 28. Intermediate 27 (0.68 g) wasthen treated with a 0.5M solution of ammonia in dioxane (17.7 ml).Diisopropylethylamine (0.51 ml) was then added and the mixture stirredfor 21 h. The mixture was then partitioned between DCM (100 ml) andwater (30 ml). An insoluble solid was removed by filtration, washed withwater (20 ml) and dried in vacuo over phosphorous pentoxide to affordIntermediate 31 (0.544 g). LCMS showed MH⁺=211; T_(RET)=1.84 min.

Intermediate 32 (=Example 3): Ethyl1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Intermediate 1 (0.20 g) and triethylamine (0.55 ml) were suspended inethanol (8 ml) and 4-aminotetrahydropyran (0.088 g) was added. Themixture was stirred under nitrogen, heated at 80° C. for 16 h, thenconcentrated in vacuo. The residue was partitioned between DCM andwater. The layers were separated and the organic layer was loadeddirectly onto an SPE cartridge (silica, 5 g) which was elutedsequentially with; (i) DCM, (ii) DCM:Et₂O (2:1), (iii) DCM:Et₂O (1:1),(iv) Et₂O and (v) EtOAc. Fractions containing desired material werecombined and concentrated in vacuo to afford Intermediate 32 (0.21 g).LCMS showed MH⁺=319; T_(RET)=2.93 min.

In an alternative embodiment, Intermediate 32 (=Example 3) can be madeas described below under “Example 3”, in particular according to“Example 3, Method B” below.

Intermediate 33:1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid

A solution of Intermediate 32 (Example 3) (0.21 g) in ethanol:water(95:5, 10 ml) was treated with sodium hydroxide (0.12 g). The mixturewas heated at 50° C. for 8 h, then concentrated in vacuo, dissolved inwater and acidified to pH 4 with acetic acid. The resultant white solidwas removed by filtration and dried under vacuum to afford Intermediate33 as an off-white solid (0.156 g). LCMS showed MH⁺=291; T_(RET)=2.11min.

An alternative preparation of Intermediate 33 is as follows:

A solution of Intermediate 32 (Example 3) (37.8 g) in ethanol:water(4:1, 375 ml) was treated with sodium hydroxide (18.9 g). The mixturewas heated at 50° C. for 5 hours, then concentrated in vacuo, dissolvedin water and acidified to pH 2 with aqueous hydrochloric acid (2M). Theresultant white solid was removed by filtration and dried under vacuumto afford Intermediate 33 as an off-white solid (29.65 g). LCMS showedMH⁺=291; T_(RET)=2.17 min.

Intermediate 34 (=Example 8): Ethyl1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Intermediate 1 (0.05 g) and (S)-(−)-3-aminotetrahydrofuran4-toluenesulphonate (0.052 g) were suspended in ethanol (1 ml) andtriethylamine (0.14 ml) was added. The mixture was stirred undernitrogen and heated at 80° C. for 24 h. After cooling to roomtemperature, ethanol was removed by evaporation under a stream ofnitrogen and the residue partitioned between DCM (2 ml) and water (1.5ml). The layers were separated and the organic layer concentrated todryness. Purification was carried out using an SPE cartridge (silica, 5g), eluting with a gradient of EtOAc:cyclohexane; (1:16 then, 1:8, 1:4,1:2, 1:1 and 1:0). Fractions containing desired material were combinedand concentrated in vacuo to afford Intermediate 34 (=Example 8) (0.052g). LCMS showed MH⁺=305; T_(RET)=2.70 min.

Similarly prepared were the following:

Amine NHR³ Reagent MH⁺ion T_(RET)(min) Intermediate 35 (= Example 9)

(R)-(+)-3- Aminotetra- hydrofuran 4-toluene- sulphonate 305 2.73Intermediate 36 (= Example 10)

Intermediate 11 335 3.21 Intermediate 37 (= Example 11)

Intermediate 12 321 3.10 Intermediate 38 (= Example 12)

Cyclo- propylamine 275 2.98

Intermediate 39 (=Example 13): Ethyl4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Intermediate 1 (0.05 g) and Intermediate 13 (0.027 g) were suspended inethanol (1 ml) and triethylamine (0.14 ml) was added. The mixture wasstirred under nitrogen and heated at 80° C. for 24 h. After cooling toroom temperature, ethanol was removed by evaporation under a stream ofnitrogen and the residue partitioned between DCM (2 ml) and water (1.5ml). The layers were separated and the organic layer concentrated todryness. Purification was carried out using an SPE cartridge (silica, 5g), eluting with a gradient of EtOAc:cyclohexane; (1:8 then 1:4, 1:2,1:1 and 1:0). Fractions containing desired material were combined andconcentrated in vacuo to afford Intermediate 39 (=Example 13) (0.045 g)as a mixture of enantiomers. LCMS showed MH⁺=353; T_(RET)=2.60 min.

Similarly prepared was the following:

Amine T_(RET) NHR³ Reagent MH⁺ion (min) Intermediate 40 (= Example 14)

Intermediate 14 367 2.64

Intermediate 41:1-Ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid

A solution of Intermediate 34 (0.037 g) in ethanol:water (95:5, 3 ml)was treated with sodium hydroxide (0.019 g). The mixture was heated at50° C. for 16 h, then concentrated in vacuo. The residue was dissolvedin water (1.5 ml) and acidified to pH 4 with acetic acid. The resultantwhite solid precipitate was removed by filtration and dried undervacuum. The filtrate was extracted with ethyl acetate and the organiclayer collected and concentrated in vacuo to afford a further portion ofwhite solid. The two solids were combined to afford Intermediate 41(0.033 g). LCMS showed MH⁺=277; T_(RET)=2.05 Similarly prepared were thefollowing:

Starting T_(RET) NHR³ Material MH⁺ion (min) Intermediate 42

Intermediate 35 277 2.05 Intermediate 43

Intermediate 36 307 2.40 Intermediate 44

Intermediate 37 293 2.59 Intermediate 45

Intermediate 38 247 2.24 Intermediate 46

Intermediate 39 325 2.05 Intermediate 47

Intermediate 40 339 2.05

Intermediate 48: Ethyl4-(cyclohexylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Intermediate 2 (0.69 g) was suspended in cyclohexylamine (1.01 ml), andthe mixture was heated at 90° C. for 3 h. The residual mixture wasallowed to cool to room temperature and partitioned between chloroform(25 ml) and water (25 ml). The phases were separated and the organicphase was evaporated to dryness. The residue was triturated with Et₂O(25 ml) and the insoluble solid was collected and dried to affordIntermediate 48 as a beige solid (0.58 g). LCMS showed MH⁺=289;T_(RET)=2.91 min.

Intermediate 49:4-(Cyclohexylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

2M-Sodium hydroxide solution (0.5 ml) was added to a stirred suspensionof Intermediate 48 (0.2 g) in dioxan (4 ml) and water (0.5 ml). Afterstirring overnight at room temperature, the reaction mixture was heatedat 40° C. for 8 h. A further quantity of 2M-sodium hydroxide solution(1.5 ml) was added, and the reaction mixture was heated at 40° C. for 48h. The reaction solution was concentrated, diluted with water (10 ml)and acidified with glacial acetic acid. The resulting precipitate wascollected by filtration, washed with water and dried to giveIntermediate 49 (0.18 g). LCMS showed MH⁺=261; T_(RET)=2.09 min.

Intermediate 50:1-n-Propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid

2M-Sodium hydroxide solution (0.7 ml) was added to a stirred suspensionof Example 185 (0.23 g, described hereinafter) in ethanol (5 ml) andwater (1.5 ml). After stirring overnight at room temperature, a furtherquantity of 2M-sodium hydroxide solution (0.7 ml) was added, and thereaction mixture was heated at 43° C. for 2.5 h. The reaction solutionwas concentrated, diluted with water (5 ml) and acidified with2M-hydrochloric acid. The resulting precipitate was collected byfiltration, washed with water and dried to give Intermediate 50 as awhite solid (0.14 g). LCMS showed MH⁺=305; T_(RET)=2.42 min.

Intermediate 51: Ethyl4-chloro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of 5-amino-1-ethylpyrazole (1.614 g, 14.5 mmol) and diethyl2-(1-ethoxyethylidene)malonate (3.68 g, 16.0 mmol, as described by P. P.T. Sah, J. Amer. Chem. Soc., 1931, 53, 1836) was heated at 150° C. underDean Stark conditions for 5 hours. Phosphorous oxychloride (25 ml) wascarefully added to the mixture and the resulting solution was heated at130° C. under reflux for 18 hours. The mixture was concentrated invacuo, then the residual oil was carefully added, with cooling, to water(100 ml). The resulting mixture was extracted with DCM (3×100 ml) andthe combined organic extracts were dried over anhydrous sodium sulphateand concentrated in vacuo. The residual oil was purified by Biotagechromatography (silica, 90 g) eluting with ethyl acetate-petrol (1:19).Fractions containing the desired product were combined and concentratedin vacuo to afford Intermediate 51 (1.15 g). LCMS showed MH⁺=268;T_(RET)=3.18 min.

Intermediate 52:4-(Cyclohexylamino)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid

2M-Sodium hydroxide solution (0.39 ml, 0.78 mmol) was added to Example190 (0.128 g, 0.39 mmol, described hereinafter) in ethanol (1.5 ml), andthe mixture was heated at 50° C. for 16 hours. The reaction mixture wasconcentrated, and the resulting aqueous solution was neutralised with2M-hydrochloric acid to precipitate a solid which was collected byfiltration. The filtrate was applied to an OASIS® hydrophilic-lipophilicbalance (HLB) Extraction cartridge * (1 g) which was eluted with waterfollowed by methanol. Evaporation of the methanol fraction gave a solidwhich was combined with the initial precipitated solid to affordIntermediate 52 (0.083 g) as a white solid, presumed to be thecarboxylic acid.

* OASIS® A HLB Extraction cartridges are available from WatersCorporation, 34 Maple Street, Milford, Mass. 01757, USA. The cartridgesinclude a column containing a copolymer sorbent having a HLB such thatwhen an aqueous solution is eluted through the column, the solute isabsorbed or adsorbed into or onto the sorbent, and such that whenorganic solvent (e.g. methanol) is eluted the solute is released as anorganic (e.g. methanol) solution. This is a way to separate the solutefrom aqueous solvent.

Intermediate 53:1-Ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid

2M-Sodium hydroxide solution (0.75 ml, 1.5 mmol) was added to Example189 (0.248 g, 0.75 mmol, described hereinafter) in ethanol (2 ml), andthe mixture was heated at reflux for 16 hours. The reaction mixture wasconcentrated, diluted with water (1 ml) and acidified with2M-hydrochloric acid (0.75 ml) to precipitate a solid which wascollected by filtration to afford Intermediate 53 (0.168 g). LCMS showedMH⁺=305; T_(RET)=1.86 min.

Intermediate 54: 4-Aminocyclohexanone hydrochloride

A solution of hydrogen chloride in dioxan (0.5 ml, 2.0 mmol, 4M) wasadded to a stirred solution of tert-butyl 4-oxocyclohexylcarbamate(0.043 g, 0.20 mmol, commercially available from Astatech Inc.,Philadelphia, USA) in dioxan (0.5 ml) and the mixture was stirred atroom temperature. After 1 h, the reaction mixture was evaporated to giveIntermediate 54 as a cream solid (34 mg). ¹H NMR (400 MHz in d₆-DMSO,27° C., δppm) 8.09 (br. s, 3H), 3.51 (tt, 11, 3.5 Hz, 1H), 2.45 (m, 2H,partially obscured), 2.29 (m, 2H), 2.16 (m, 2H), 1.76 (m, 2H).

Intermediate 54A:N-Benzyl-4-(cyclohexylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Benzylamine (0.16 ml) was added to a stirred mixture of Intermediate 49(0.13 g), DIPEA (0.26 ml) and HATU (0.285 g) in DMF (3 ml). Theresultant mixture was heated with stirring at 85° C. for 16 hours.Further portions of HATU (0.14 g), DIPEA (0.13 ml) and benzylamine(0.082 ml) were added and the mixture heated for 16 hours at 88° C. Theresultant solution was concentrated, diluted with dichloromethane (20ml) and washed with saturated sodium bicarbonate solution (20 ml),separated by hydrophobic frit and the organic layer concentrated. Theresidue was purified on a SPE cartridge (silica, 20 g) eluting with60-80% ethyl acetate in cyclohexane. The residue was purified further ona SPE cartridge (Isolute SCX sulphonic acid cartridge, 5 g×2), elutingwith methanol (2×20 ml) and 10% ammonia in methanol (4×20 ml); the basicfractions were combined and concentrated to give Intermediate 54A as awhite solid (0.07 g). LCMS showed MH⁺=350; T_(RET)=2.99 min.

Intermediate 55:4-Chloro-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

That is, Intermediate 55 is:

Intermediate 15 (1.04 g) was treated with thionyl chloride (13.22 g).The mixture was stirred and heated at 75° C. for 2 h. Excess thionylchloride was removed in vacuo and the residual oil azeotroped withtoluene to afford Intermediate 16, presumed to be the acid chloridederivative of intermediate 15, as a cream solid (1.12 g).

Intermediate 16 (0.997 g) was dissolved in tetrahydrofuran (THF) (25 ml)and treated with N,N-diisopropylethylamine (1.07 ml) then with1-[4-(methyloxy)phenyl]methanamine 4-methoxybenzylamine (0.54 ml)(obtainable from e.g. Aldrich, Acros, or Tetrahedron Lett., 2002,43(48), 8735; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; orOrganic Letters, 2002, 4(12), 2055) and the mixture was stirred for 3 h.The solution was concentrated in vacuo, then partitioned between DCM andwater. The layers were separated and the organics concentrated in vacuo.The solid was then triturated in 1:1 ethyl acetate: cyclohexane to giveIntermediate 55 (1.27 g). LCMS showed MH⁺=345, T_(RET)=2.86 min.

Similarly prepared were the following:

Source of NR⁴Rhu 5 HNR⁴R⁵ MH⁺ ion T_(RET) (min) Intermediate 56

Lis et al., J Med. Chem., 1990, 33(10), 2883, see Scheme III and ref. 24408 2.60 Intermediate 57

Maybridge-Int; or Aldrich; or TCI-America 341 3.08

Intermediate 58:1-Ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid

A solution of sodium hydroxide (0.053 g, 1.32 mmol) in water (0.41 ml)was added to a stirred solution of Example 205 (0.1 g, 0.303 mmol) inethanol (1 ml), and the resulting mixture was heated at 50° C. After 1h, the cooled reaction mixture was adjusted to pH3 with 2M hydrochloricacid, and extracted with EtOAc (2×6 ml). The combined organic extractswere dried (Na₂SO₄) and evaporated to give Intermediate 58 (0.072 g) asa white solid. LCMS showed MH⁺=303; T_(RET)=2.13 min.

An alternative preparation of Intermediate 58 is as follows:

A solution of sodium hydroxide (0.792 g, 19.8 mmol) in water (6 ml) wasadded to a stirred solution of Example 205 (1.487 g, 4.5 mmol) inethanol (15 ml), and the resulting mixture was heated at 50° C. After 1hour, the cooled reaction mixture was adjusted to pH4 with 2Mhydrochloric acid, and extracted with EtOAc (3×30 ml). The combinedorganic extracts were dried (Na₂SO₄) and evaporated to give Intermediate58 (1.188 g) as a white solid. LCMS showed MH⁺=303; T_(RET)=2.12 min.

Intermediate 58A: Ethyl1-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Intermediate 1 (0.76 g, 3.0 mmol)) was dissolved in acetonitrile (10ml). Tetrahydro-2H-pyran-3-amine hydrochloride (0.5 g, 3.6 mmol, AnalesDe Quimica, 1988, 84, 148) and N,N-diisopropylethylamine (3.14 ml, 18.0mmol) were added and the mixture was stirred at 85° C. for 24 h. After24 h a further portion of tetrahydro-2H-pyran-3-amine hydrochloride(0.14 g, 1.02 mmol) was added and stirring was continued at 85° C. Aftera further 8 h, the mixture was concentrated in vacuo. The residue waspartitioned between DCM (20 ml) and water (12 ml). The layers wereseparated and the aqueous layer was extracted with further DCM (12 ml).The combined organic extracts were dried (Na₂SO₄), and concentrated invacuo to give a brown solid which was purified on a SPE cartridge(silica, 20 g) eluting with a gradient of ethyl acetate:cyclohexane(1:16, 1:8, 1:4, 1:2, 1:1, 1:0). Fractions containing the desiredmaterial were combined and evaporated to afford Intermediate 58A (0.89g). LCMS showed MH⁺=319; T_(RET)=2.92 min.

Intermediate 59:1-Ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid

A solution of Intermediate 58A (0.89 g, 2.79 mmol) in ethanol (16.7 ml)was treated with sodium hydroxide (0.47 g, 11.7 mmol) as a solution inwater (3.1 ml). The mixture was stirred at 50° C. After 12 h, thereaction mixture was concentrated in vacuo to give a residual oil whichwas dissolved in water (16 ml), then cooled and acidified to pH 3 with2M hydrochloric acid. After stirring at 0° C. for 30 min, the resultingprecipitate was collected by filtration, washed with cooled water (2 ml)and dried in vacuo to afford Intermediate 59 as a white solid (0.73 g).LCMS showed MH⁺=291; T_(RET)=2.19 min.

Intermediate 60:4-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid

Aqueous sodium hydroxide solution (8.55 ml, 2M) was added to a solutionof Example 207 (1.55 g) in EtOH (13 ml). The mixture was heated at 50°C. for 18 h then neutralised using aqueous hydrochloric acid andevaporated in vacuo to afford a mixture of1-ethyl-4-(4-piperidinylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid and4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid Acetic acid (0.36 ml) was added to a stirred mixture of HATU (2.41g) and N,N-diisopropylethylamine (2.21 ml) in N,N-dimethylformamide (65ml). After stirring for 15 min the mixture was added to the mixture of1-ethyl-4-(4-piperidinylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid and4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid and the reaction stirred for 15 h. The reaction mixture wasevaporated in vacuo and the residue purified by chromatography usingBiotage (silica 90 g) eluting with DCM: MeOH (0%-5% MeOH) to affordIntermediate 60 (1.36 g) as a white solid. LCMS showed MH⁺=334;T_(RET)=2.06 min.

Intermediate 61:4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

A solution of Example 2 (5.37 g, 17 mmol) in ethanol (30 ml) was treatedwith a solution of sodium hydroxide (2.72 g, 68 mmol) in water (20 ml),and the resulting mixture was stirred at 50° C. for 3 h. The reactionmixture was concentrated in vacuo, dissolved in water (250 ml) and thecooled solution was acidified to pH 1 with 5M-hydrochloric acid. Theresultant solid was collected by filtration and dried in vacuo to affordIntermediate 61 as a white solid (4.7 g). LCMS showed MH⁺=289;T_(RET)=2.83 min.

Intermediate 62: 1,1-Dimethylethyl (4,4-difluorocyclohexyl)carbamate

(Diethylamino)sulphur trifluoride (DAST), (0.06 ml, 0.47 mmol), wasadded to a stirred solution of1,1-dimethylethyl(4-oxocyclohexyl)carbamate, (250 mg, 1.17 mmol,commercially available from AstaTech Inc., Philadelphia, USA) inanhydrous dichloromethane (5 ml) and the mixture was stirred undernitrogen at 20° C. After 22 h, the reaction mixture was cooled to 0° C.,treated with saturated sodium hydrogen carbonate solution (4 ml), andthen allowed to warm to ambient temperature. The phases were separatedby passage through a hydrophobic frit and the aqueous phase was furtherextracted with DCM (5 ml). The combined organic phases were concentratedin vacuo to give an orange solid (369 mg) which was further purified bychromatography using a SPE cartridge (silica, 10 g), eluting with DCM toafford Intermediate 62 (140 mg) containing 20% of 1,1-dimethylethyl(4-fluoro-3-cyclohexen-1-yl)carbamate. ¹H NMR (400 MHz in CDCl₃, 27° C.,δppm) Minor component: δ5.11 (dm, 16 Hz, 1H), 4.56 (br, 1H), 3.80 (br,1H) 2.45-1.45 (m's, 6H excess), 1.43 (s, 9H). Major component: δ4.43(br, 1H), 3.58 (br, 1H), 2.45-1.45 (m's, 8H excess), 1.45 (s, 9H).

Intermediate 63: (4,4-Difluorocyclohexyl)amine hydrochloride

A solution of hydrogen chloride in dioxane (4M, 1.6 ml) was added at 20°C. to a stirred solution of Intermediate 62 (140 mg, 0.6 mmol), indioxane (1.6 ml). After 3 h, the reaction mixture was concentrated invacuo to afford intermediate 63 (96.5 mg) containing4-fluoro-3-cyclohexen-1-amine. ¹H NMR (400 MHz in d₆-DMSO, 27° C., δppm)Minor component: δ8.22 (br, 3H excess), 5.18 (dm, 16 Hz, 1H), 3.28-3.13(m, 1H excess), 2.41-1.53 (m's, 6H excess). Major component: δ8.22 (br,3H excess), 3.28-3.13 (m, 1H excess), 2.41-1.53 (m's, 8H excess).Impurities are also present.

Intermediate 64:4-Chloro-1-ethyl-N-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Intermediate 15 (0.06 g, 0.266 mmol) was treated with thionyl chloride(0.48 ml). The mixture was stirred and heated at 75° C. for 2 h. Excessthionyl chloride was removed in vacuo and the residual oil azeotropedwith dichloromethane (DCM) to afford Intermediate 16, presumed to be theacid chloride derivative of Intermediate 15, as a white solid.Intermediate 16 was dissolved in anhydrous tetrahydrofuran (THF) (2 ml)and treated with N,N-diisopropylethylamine (DIPEA) (0.069 ml), then withmethylamine (2M in tetrahydrofuran, 0.15 ml) and the mixture stirredunder nitrogen for 16 h. A further 0.05 ml of methylamine (2M in THF)was added and the solution stirred for 2 h. The mixture was concentratedin vacuo, then partitioned between dichloromethane (2 ml) and aqueoussodium hydroxide solution (2M, 2 ml), then the organic layer washed withwater (2 ml). The layers were separated and the organics concentrated invacuo to afford Intermediate 64 (0.052 g). LCMS showed MH⁺=239;T_(RET)=2.17 min.

Intermediate 65: Ethyl4-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of Intermediate 17 (2.0 g, 6.37 mmol), 1,1-dimethylethyl4-amino-1-piperidinecarboxylate (2.04 g, 10.2 mmol) andN,N,-diisopropylethylamine (5.54 ml, 31.9 mmol) in MeCN (40 ml) washeated at 85° C. for 42 h. The reaction was evaporated and the residuespartitioned between DCM and water. The organic phase was dried (MgSO₄)then evaporated in vacuo. The residue was chromatographed on silica(Biotage, 90 g) eluting with cyclohexane:EtOAc (1:1) to giveIntermediate 65 as a white solid (2.70 g). LCMS showed MH⁺=479;T_(RET)=3.37 min.

Intermediate 67: 3-Amino-N-cyclohexyl-N-methylbenzamide

A solution of 3-nitrobenzoyl chloride (2.0 g, 10.78 mmol) in DCM (20 ml)was added dropwise to a stirred mixture of N-methylcyclohexylamine (1.83ml, 14.01 mmol), N,N,-diisopropylethylamine (3.76 ml, 21.56 mmol) andN,N-dimethylaminopyridine (0.01 g) in DCM at 20° C. The reaction mixturewas stirred for 56 h then evaporated in vacuo. The residue waspartitioned between ethyl acetate and water. The organic phase waswashed with aqueous HCl then dried (MgSO₄) and evaporated in vacuo. Theresidue was purified by chromatography on silica eluting withcyclohexane:EtOAc (9:1 followed by 2:1) to affordN-cyclohexyl-N-methyl-3-nitrobenzamide (1.40 g). MS showed MH⁺ 263.

A mixture of N-Cyclohexyl-N-methyl-3-nitrobenzamide (1.40 g, 5.35 mmol)and palladium on carbon (5%, 0.140 g) in ethanol (10 ml) was stirredunder an atmosphere of hydrogen for 1 hour. The reaction mixture wasfiltered through Celite and the filtrate evaporated to affordIntermediate 67 as a brown solid (0.107 g). LCMS showed MH⁺=233;T_(RET)=2.56 min.

Intermediate 68: N-Ethyl-4-oxo-1-piperidinecarboxamide

A solution of ethyl isocyanate (2.31 g, 32.5 mmol) in DCM (40 ml) wasadded, dropwise over 15 min, to a vigorously stirred solution of4-piperidone monohydrate hydrochloride (5.0 g, 32.5 mmol, commerciallyavailable from Aldrich) and sodium hydrogen carbonate (8.2 g, 97.5 mmol)in water (60 ml) at 0° C. The reaction mixture was stirred at roomtemperature for 20 h. Sodium chloride (7.0 g) was added to the reactionmixture and the organic phase was separated. The aqueous phase wasextracted with further DCM (3×75 ml). The combined organic extracts weredried (Na₂SO₄) and evaporated in vacuo to give a white solid (4.0 g).Recrystallisation from ethyl acetate: cyclohexane (10:1) affordedIntermediate 68 as a white solid (2.3 g).

TLC (silica) gave R_(f)=0.24 (ethyl acetate). Anal. Found: C, 56.7; H,8.3; N, 16.35. C₈H₁₄N₂O₂ requires C, 56.5; H, 8.3; N, 16.5.

Intermediate 69: 4-Amino-N-ethyl-1-piperidinecarboxamide

A solution of Intermediate 68 (1.5 g, 8.8 mmol) and benzylamine (1.04 g,9.7 mmol) in absolute ethanol (60 ml) was hydrogenated over pre-reduced10% palladium on charcoal catalyst (0.6 g) in ethanol (20 ml) until theuptake of hydrogen had ceased (22 h). The reaction mixture was filteredthrough filter agent (Celite), and then through silica gel (100 ml)eluting with ethanol:0.88-ammonia (100:1) to give a black oil. The oilwas dissolved in ethanol (30 ml) and treated with a solution of hydrogenchloride in ethanol (3M) until the solution was acidic. The solvent wasevaporated and the residue was triturated with ethanol to affordIntermediate 69 as a white solid (1.09 g).

TLC (silica) gave R_(f)=0.73 (ethyl acetate:methanol, 10:1). Anal.Found: C, 45.9; H, 8.4; N, 19.8. C₈H₁₈ClN₃O requires C, 46.3; H, 8.7; N,20.2.

Intermediate 70: 1,1-Dimethylethyl({4-[(cyclopropylamino)carbonyl]phenyl}methyl)carbamate

Cyclopropylamine (0.136 g, 2.39 mmol) and diisopropylethylamine (0.68ml, 3.9 mmol) were added to a stirred solution of4-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)-methyl]benzoic acid (0.501g, 2.0 mmol), EDC (0.612 g, 3.2 mmol) and HOBT (0.35 g, 2.6 mmol) in DMF(2 ml). The resulting mixture was stirred at room temperature overnight.Solvents were removed in vacuo, and the residue was dissolved in ethylacetate (20 ml) and washed with 0.5M-hydrochloric acid (3×20 ml). Theorganic phase was dried (Na₂SO₄) and evaporated in vacuo to give thecrude product which was purified by Biotage chromatography (silica)eluting with ethyl acetate:cyclohexane (1.3:1) to afford Intermediate 70as a white solid (0.512 g). LCMS showed MH⁺=291; T_(RET)=2.75 min.

Intermediate 71: 4-(Aminomethyl)-N-cyclopropylbenzamide hydrochloride

Intermediate 70 (0.506 g, 1.74 mmol) was dissolved in a solution ofhydrogen chloride in dioxan (20 ml, 4M) under nitrogen. After 1 h,methanol (3 ml) was added to the mixture and stirring was continued atroom temperature overnight. Solvents were removed in vacuo to affordIntermediate 71 as a white solid (0.416 g). LCMS showed MH⁺=191;T_(RET)=0.82 min.

Intermediate 72

Intermediate 33 (1.36 g, 4.7 mmol), EDC (1.26 g, 6.57 mmol) and HOBT(0.76 g, 5.62 mmol) were suspended in DMF (50 ml) and stirred vigorouslyat room temperature for 0.5 h, before adding 1,1-dimethylethyl4-(aminomethyl)-1-piperidinecarboxylate (1.3 g, 6.07 mmol, commerciallyavailable from Maybridge Chemical Co. Ltd.,). After stirring at roomtemperature overnight, a further quantity of 1,1-dimethylethyl4-(aminomethyl)-1-piperidinecarboxylate (1.01 g, 4.7 mmol) was added tothe reaction mixture which was then heated at 50° C. After 6 h,diisopropylethylamine (0.25 ml, 1.44 mmol) was added, and the mixturewas maintained at 50° C. for a further 6 h. Solvents were removed invacuo and the residue was partitioned between DCM (100 ml) and water (10ml). The phases were separated by passage through a hydrophobic frit,and the organic phase was evaporated in vacuo to give the crude product.Further purification using SPE cartridges (aminopropyl followed bysilica) afford Intermediate 72 as a cream solid (1.24 g). LCMS showedMH⁺=487; T_(RET)=2.97 min.

Intermediate 73

Intermediate 73 is used in situ in the general procedure for Examples360-414.

Intermediate 74: 1,1-Dimethylethyl({3-[(acetylamino)methyl]phenyl}methyl)carbamate

Acetic anhydride (0.52 ml, 5.5 mmol) was added to a mixture oftert-butyl N-β-aminomethyl)benzyl] carbamate (1.1 g, 4.65 mmolcommercially available from Astatech) and triethylamine (0.7 ml, 5 mmol)in THF (20 ml). The reaction mixture was stirred at 20° C. from 16 hthen concentrated in vacuo. The residue was partitioned between EtOAcand water. The organic phase was dried (MgSO₄) and evaporated in vacuo.The residue was chromatographed over silica eluting with hexanes:EtOAc(1:1) followed by EtOAc to afford Intermediate 74 (1.2 g) as acolourless oil. Anal. Found: C, 64.79; H, 7.93; N, 10.10. C₁₅H₂₂N₂O₃requires C, 64.73; H, 7.97; N, 10.06. MS (M+Na)⁺ 301.

Intermediate 75: N-{[3-(Aminomethyl)phenyl]methyl}acetamidehydrochloride

Hydrogen chloride in dioxane (4 ml, 4M) was added to a solution ofIntermediate 74 (1.0 g, 3.6 mmol) in dioxane (10 ml) and the resultantmixture stirred for 6 hours at 20° C. The reaction was diluted with Et₂O(20 ml) and filtered to afford Intermediate 75 (0.7 g) as a white solid.MS MH⁺ 179. ¹H NMR (300 MHz in d6-DMSO, 27° C., δppm) δ 8.6-8.4 (br m,3H), 7.38-7.26 (m, 3H), 7.22 (bm, 1H), 4.24 (d, J=5.7 Hz, 2H), 3.95 (dd,J=11.6, 5.7 Hz, 2H), 1.87 (s, 3H).

Intermediate 761-Ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid

(cis-3-hydroxycyclohex-1-ylamino group, racemic)

A solution of Example 665 (0.681 g, 2.05 mmol) in ethanol (7 ml) wastreated with a solution of sodium hydroxide (0.362 g, 9.05 mmol) inwater (2.9 ml). The resulting mixture was stirred at 50° C. After 3 h,the reaction mixture was concentrated in vacuo to give a residual oilwhich was dissolved in water (3 ml), then cooled and acidified to pH 3with 2M-hydrochloric acid. After stirring at 0° C. for 1 h, theresulting precipitate was collected by filtration, washed with cooledwater (0.5 ml) and dried in vacuo to afford Intermediate 76 as a whitesolid (0.491 g). LCMS showed MH⁺=305; T_(RET)=2.14 min. Table ofExamples Example Number Name 1 Ethyl4-(cyolopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 2Ethyl4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 3Ethyl1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 5 Ethyl4-[(1-acetylpiperidin-4-yl)amino]1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 6 Ethyl4-(cyclopentylamino)-1-methyl-1H-pyrazolo',4-b]pyridine-5-carboxylate 7Ethyl1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 8 Ethyl1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 9 Ethyl1-ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 10 Ethyl1-ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 11 Ethyl1-ethyl-4-(tetrahydrothien-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 12 Ethyl4-(cyolopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 13Ethyl 4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-1-ethy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 14 Ethyl4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 21N-Benzyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pryazolo[3,4-b]pyridine-5-carboxamide 221-Ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pryazolo[3,4-b]pyridine-5-carboxamide 23N-Cyclopentyl-4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 244-(Cyclohexylamino)-N-cyclopentyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 25N-Cyclopentyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 274-[(1-Acetylpiperidin-4-yl)amino]-N-cyclopentyl-1-ethyl-1H-pyrazolo[3,4-b)pyridine-5-carboxamide 28N-Cyclopentyl-1-ethyl-5-(pyrrolidin-1-ylcarbonyl)-1H-pyrazolo[3,4-b]pyridin-4-amine 29N-Cyclohexyl-1-ethyl-5-(pyrrolidin-1-ylcarbonyl)-1H-pyrazolo[3,4-b]pyridin-4-amine 301-Ethyl-5-(pyrrolidin-1-ylcarbonyl)-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine 314-(Cyclopentylamino)-1-ethyl-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 324-(Cyolohexylamino)-1-ethyl-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 331-Ethyl-N-(pyridin-4-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolol[3,4-b]pyridine-5-carboxamide 344-(Cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 354-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 361-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 39N-Benzyl-4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 40N-Benzyl-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 414-[(1-Acetylpiperidin-4-yl)amino]-N-benzyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 424-(Cyclopentylamino)-1-ethyl-N-(2-ethylbutyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 434-(Cyclohexylamino)-1-ethyl-N-(2-ethylbutyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 441-Ethyl-N-(2-ethylbutyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 451-Ethyl-N-(2-ethylbutyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 464-(1-Acetylpiperidin-4-yl)amino]-1-ethyl-N-(2-ethylbutyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 474-(Cyclopentylamino)-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 484-(Cyclohexylamino)-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 491-Ethyl-N-(4-fluorophenyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 504-[(1-Acetylpiperidin-4-yl)amino]-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 514-(Cyclopentylamino)-1-ethyl-N-n-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 524-(Cyclohexylamino)-1-ethyl-N-n-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 531-Ethyl-N-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 554-[(1-Acetylpiperidin-4-yl)amino]-1-ethyl-N-n-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 574-[(1-Acetylpiperidin-4-yl)amino]-1-ethyl-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 61N-Benzyl-4-(cyolopentylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 62N-Benzyl-4-(cyclohexylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 63N-Benzyl-1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 644-(Cyclopentylamino)-N-(2-ethylbutyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 654-(Cyclohexylamino)-N-(2-ethylbutyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 66N-(2-Ethylbutyl)-1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 674-(Cyclopentylamino)-N-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 684-(Cyclohexylamino)-N-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 69N-(4-Fluorophenyl)-1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 704-(Cyclopentylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide71 4-(Cyclohexylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide74 4-[(1-Acetylpiperidin-4-yl)amino]-N-benzyl-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 811-Ethyl-N-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 821-Ethyl-N,N-dimethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 831-Ethyl-N-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 841-Ethyl-N-isopropyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 85N-Benzyl-1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 86N-Benzyl-1-ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 87N-Benzyl-1-ethyl-4-(tetrahydrothien-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 88N-Benzyl-4-(cyclopropylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 89N-Benzyl-4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 90N-Benzyl-4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-1H-pyrazolol[3,4-b]pyridine-5-carboxamide 91N-Benzyl-1-ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 921-Ethyl-N-(4-fluorophenyl)-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 931-Ethyl-N-(4-fluorophenyl)-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 941-Ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolol[3,4-b]pyridine-5-carboxamide 951-Ethyl-N-(4-fluorophenyl)-4-(tetrahydrothien-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 964-(Cyclopropylamino)-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 974-[(1,1-Dioxidotetrahydrothien-3-yl)amino]-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 984-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1001-Ethyl-N-[4-(methylsulfonyl)benzyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1021-Ethyl-N-[3-(methylsulfonyl)benzyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1031-Ethyl-5-{[5-methoxy-6-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine 104N-[(5-Chloropyridin-2-yl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 105N-(4-Chlorohenzyl)-1-ethyl-N-isopropyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-h]pyridine-5-carboxamide 106N-(3-Chlorohenzyl)-1-ethyl-N-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1071-Ethyl-N-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 108N-(2-tert-Butoxyethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1091-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(1,3-thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1101-Ethyl-N-(pyrimidin-4-ylmethyl)-4-(tetrahydro-2H-pyan-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1111-Ethyl-N-[(2-methyl-1,3-thiazo1-4-yl)methyl]-4-(tetrahydro-2H-pyra-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 112N-[3-(tert-Butoxymethyl)benzyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1131-Ethyl-N-{2-[methyl(methylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1141-Ethyl-N-(pyrazin-2-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1151-Ethyl-5-{[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]carbonyl}-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine 116N-(2-Chloro-6-fluorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1171-Ethyl-N-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 118N-[3-(Aminocarbonyl)benzyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1191-Ethyl-N-{4-[(methylamino)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1201-Ethyl-N-[2-(1-methyl-1H-imidazol-4-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 121N-{2-[(Anilinocarbonyl)amino]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1221-Ethyl-N-(1H-tetraazol-5-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-caxboxamide hydrochloride 1231-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1251-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 126tert-Butyl 4-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)piperidine-1-carboxylate 1271-Ethyl-N-{3-[(methylsulfonyl)amino]propyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 128N-[2-(Dimethylamino)benzyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1291-Ethyl-N-[(1-ethylpyrolidin-2-yl)methyl]-4-(tehydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1301-Ethyl-N-(tetrahydrofuran-2-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1311-ethyl-N-tetrahydro-2H-pyran-4-yl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 132N-{4-[(Dimethylamino)sulfonyl]benzyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1331-Ethyl-N-{3-[(methylsulfonyl)amino]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1351-Ethyl-N-(4-methoxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1361-Ethyl-N-[3-(2-oxopyrrolidin-1-yl)propyl]-4-(tetrahydro-2H-pyran-4-ylamino-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1371-Ethyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1381-Ethyl-N-(pyridin-3-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-8]pyridine-5-carboxamide 1391-Ethyl-N-(1-methylpiperidin-4-yl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1401-Ethyl-N-(1-ethylpropyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1411-Ethyl-N-(2-piperidin-1-ylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1421-Ethyl-N-(3-morpholin-4-ylpropyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 143N-(3-Ethoxypropyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylaminoy-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 144N-(Cyclohexylmethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 145N-[3-(Dimethylamino)propyly]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1461-Ethyl-N-neopentyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1471-Ethyl-N-(4-methoxybenzyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1481-Ethyl-N-{2-[(phenylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 149N-[2-(Acetylamino)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1501-Ethyl-N-{2-[(methylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1521-Ethyl-N-{2-[(2-methoxyphenyl)(methyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1531-Ethyl-N-(2-oxo-2-phenylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 154N-(2,5-Difluorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1551-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 156N,1-Diethyl-N-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 157N-Cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 158N-(2-amino-2-oxoethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1591-Ethyl-N-(3-methoxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 160N-(3,4-Difluorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 161 Ethyl3-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)propanoate 162N-(1-Benzylpiperidin-4-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 163N-Butyl-4-{[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}piperazine-1-carboxamide 1641-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(1,3,4-thiadiazol-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 165N-(2,3-Dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1661-Ethyl-N-[2-(2-oxoimidazolidin-1-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 167N-(3,4-Dimethoxybenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b)pyridine-5-carboxamide 168N-(3-Chlorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1691-Ethyl-5-[(4-methylpiperazin-1-yl)carbonyl]-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine 1701-Ethyl-N-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1711-Ethyl-5-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine 1721-Ethyl-N-{4-[(methylsulfonyl)methyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 173N-[3-(dimethylamino)-3-oxopropyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1741-Ethyl-N-[(1-methyl-1H-imidazol-5-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pryidine-5-carboxamide 1751-Ethyl-N-{4-[(methylamino)sulfonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 176N-(2-Cyanoethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1781-Ethyl-N-[(1-methyl-1H-pyrazo1-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1791-Ethyl-N-methyl-N-[(1-methyl-1H-imidazo1-2-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1801-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(2-thien-2-ylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 181N-[2-(4-Chlorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1821-Ethyl-N-[2-(2-methoxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 183 Ethyl4-(cyclohexylamino)-1-(3-ethoxy-3-oxopropyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 185 Ethyl1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 186 Ethyl1-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 187N-[4-(Methylsulfonyl)benzyl]-1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 188N-(4-Fluorophenyl)-1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 189 Ethyl1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 190 Ethyl4-(cyclohexylamino)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 1914-(Cyclohexylamino)-1-ethyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 192N-Benzyl-4-(cyclohexylamino)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1934-(Cyclohexylamino)-1-ethyl-N-(4-fluorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1944-(Cyclohexylamino)-1-ethyl-6-methyl-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 1954-(Cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 196N-Benzyl-1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Hpyrazolo[3,4-b]pyridine-5-carboxamide 197N-Benzyl-1-ethyl-4-[(2-oxoazepan-3-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 198N-Benzyl-1-ethyl-4-[(3-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide; also calledN-benzyl-1-ethyl-4-[(3-hydroxycyclohexan-1-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 199N-Benzyl-1-ethyl-4-(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide; also calledN-benzyl-1-ethyl-4-[(4-hydroxycyclohexan-1-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 200N-Benzyl-1-ethyl-4-[(3-hydroxycyclopentyl)amino-]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide; also calledN-benzyl-1-ethyl-4-[(3-hydroxycyclopentan-1-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 201N-Benzyl-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide; also calledN-Benzyl-1-ethyl-4-[(4-oxocyclohexan-1-yl)amino]-1H-pyrazolol[3,4-b]pyridine-5-carboxamide 2021-Ethyl-N-(2-hydroxy-1-methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 203 Methyl(2-S)-2-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolol[3,4-b]pyridin-5-yl]carbonyl}amino)-3-hydroxypropanoate 204Ethyl1-ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate205 Ethyl1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate207 Ethyl4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate209 Ethyl4-[(4-aminocyclohexyl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate210Ethyl-N-[(1-oxido-3-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2111-Ethyl-N-[(1-oxido-2-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2121-Ethyl-N-[(1-oxido-4-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2144-[(cis-4-Aminocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2214-(Cyclobutylamino)-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide2224-(Cycloheptylamino)-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2231-Ethyl-4-[(4-methylcyclohexyl)amino]-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2241-Ethyl-4-[(3-methylcyclohexyl)amino]-N-(phenylmethyl)-1H-pyrazolo[3,4b]pyridine-5-carboxamide 2251-Ethyl-4-[(3-methylcyclohexyl)amino]-N-(phenylmethyl)-1H-pyrazolo[3,4b]pyridine-5-carboxamide 2264-[(1R,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2274-[(1R,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2281-Ethyl-4-{[(3S)-2-oxo-3-pyrrolidinyl]amino}-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2294-[(2,5-Dioxo-3-pyrrolidinyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2304-(1-Azabicyclo[2.2.2]oct-3-ylamino)-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2311-Ethyl-4-[(1-methylcyclohexyl)amino]-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2334-(Cyclobutylamino)-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2344-(Cycloheptylamino)-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2354-[(1R,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-{([4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2361-Ethyl-4-[(4-methylcyclohexyl)amino]-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2371-Ethyl-4-[(3-methylcyclohexyl)amino]-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2384-[(1R,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2394-[(cis-4-Aminocyclohexyl)amino]-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2404-(Cyoloheptylamino)-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2414-(Cyclobutylamino)-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2424-[(1R,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2434-[(1R,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo [3,4-b]pyridine-5carboxamide 2441-Ethyl-4-[(4-methylcyclohexyl)amino}-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2451-Ethyl-4-[(3-methyloyclohexyl)amino]-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2471-Ethyl-4-(1-methylclohexyl)amino]-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo(3,4-b]pyridine-5-carboxamide 2484-[(cis-4-Aminocyolohexyl)amino]-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2494-(Cyclohexylamino)-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2504-(Cycloheptylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2514-(Cyclobutylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 253N-(2,3-Dihydro-1H-inden-2-yl)-1-ethyl-4-[(3-methylcyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 254N-(2,3-Dihydro-1H-inden-2-yl)-1-ethyl-4-[(4-methylcyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2554-[(1R,2R,4S)-Bicyclo[2.2.1]hept-2-ylamino]-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2564-[(1R,2S,4S)-Bicyclo[2.2.1]hept-2-ylamino]-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 257N-(2,3-Dihydro-1H-inden-2-yl)-1-ethyl-4-[(1-methylcyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2584-[(cis-4-Aminocyclohexyl)amino]-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2591-Ethyl-N-{4-[(methylsulfonyl)methyl)phenyl}-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 260N-[(2,4-Dimethylphenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 261N-[(3,4-Dimethylphenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 262N-[(3,4-Dichlorophenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2631-Ethyl-N-{[4-(methyloxy)phenyl-methyl}-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2641-Ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 265N-{[4-(Dimethylamino)phenyl]methyl}-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 266N-({4-[(Difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2671-Ethyl-4-[(4-oxocyclohexyl)amino]-N-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2681-Ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2691-Ethyl-N-(4-fluorophenyl)-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2701-Ethyl-4-[(4-oxocyclohexyl)amino]-N-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 271N-(2,3-Dihydro-1H-inden-2-yl)-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 272N-(1-Acetyl-4-piperidinyl)-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b-pyridine-5-carboxamide 2731-Ethyl-N-[(1-methyl-1H-pyrazo1-4-yl)methyl]-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 274N,1-Diethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4b]pyridine-5-carboxamide2751-Ethyl-4-[(4-oxocyclohexyl)amino]-N-(1,3-thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2761-Ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine- 5-carboxamide 277N-({4-[(Difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2781-Ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-N-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2791-Ethyl-N-{[4-(methylsulfonyl)phenyl]methyl)}-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2801-Ethyl-N-{4-[(methylsulfonyl)methyl]phenyl}-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2811-Ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4b]pyridine-5-carboxamide 2821-Ethyl-N-(2-pyridinylmethyl)-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4b]pyridine-5-carboxamide trifluoroacetate 283N-(2,3-Dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 284N-(1-Acetyl-4-piperidinyl)-1-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4b]pyridine-5-carboxamide 2851-Ethyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 286N,1-Diethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide2871-Ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-N-(1,3-thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2884-[(4,4-Difluorocyclohexyl)amino]-1-ethyl-N-phenylmethyl)-1H-pyrazolo[3,4-b]pyridine5-carboxamide 2891-Ethyl-4-[(4-fluoro-3-cyclohexen-1-yl)amino]-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide. 2904-[(1-Acetyl-4-piperidenyl)amino]-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2914-[(1-Acetyl-4-piperidinyl)amino]-N-[(3,4-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2924-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-[(3-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2934-[(1-Acetyl-4-piperidinyl)amino]-N-[(3,4-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2944-[(1-Acetyl-4-piperidinyl)amino]-N-[(2,5-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2954-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-{[3-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2964-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2974-[(1-Acetyl-4-piperidinyl)amino]-N-[(2,6-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2984-[(1-Acetyl-4-piperidinyl)amino]-N-[(3-chlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 2994-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3004-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-{[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3014-[(1-Acetyl-4-piperidinyl)amino]-N-({4-[dimethylamino)sulfonyl]phenyl}methyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3024-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3034-[(1-Acetyl-4-piperidinyl)amino]-N-{[2-(dimethylamino)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3044-[(1-Aeetyl-4-piperidinyl)amino]-N-[(2,4-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3054-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3064-[(1-Acetyl-4-piperidinyl)amino]-N-[(2-chloro-6-fluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3074-[(1-Acetyl-4-piperidinyl)amino]-N-({4-[(difluoromethyl)oxy]phenyl}methyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3084-[(1-Acetyl-4-piperidinyl)amino]-N-{[3-chloro-4-(methyloxy)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3094-[(1-Acetyl-4-piperidinyl)amino]-N-[(5-chloro-2-pyridinyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3104-(1-Acetyl-4-piperidinyl)amino]-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3114-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-(1,3-thiazo1-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3124-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3134-[(1-Acetyl-4-piperidinyl)amino]-N-(2,2-diphenylethyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3144-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3154-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3164-[(1-Acetyl-4-piperidinyl)amino]-N-{[4-(aminosulfonyl)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3174-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-({3-[(methylamino)carbonyl]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3184-[(1-Acetyl-4-piperidinyl)amino]-N-{[4-(aminocarbonyl)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3194-[(1-Acetyl-4-piperidinyl)amino]-1-ethyl-N-{[6-(methyloxy)-3-pyridinyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3201-Ethyl-N-4-pipenyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3211-Ethyl-N-(4-piperidinylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3221-Ethyl-N-[1-(ethylsulfonyl)-4-piperidinyl]4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3231-Ethyl-N-{1-[(1-methylethyl)sulfonyl]-4-pipeiridinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 324N-[1-(Cyclopentylsulfonyl)-4-piperidinyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3251-Ethyl-N-[1-(methylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3261-Ethyl-N-{1-[(phenylmethyl)sulfonyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo(3,4-b]pyridine-5-carboxamide 3271-Ethyl-N-[1-(phenylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3281-Ethyl-N-[1-(propylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 329N-[1-(Cyclopropylcarbonyl)-4-piperidinyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3301-Ethyl-N-[1-(3-furanylcarbonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 331N-[1-(3,3-Dimethylbutanoyl)-4-piperidinyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3321-Ethyl-N-[1-(2-ethylbutanoyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 333N-[1-(Cyclopentylacetyl)-4-piperidinyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3341-Ethyl-N-[1-(2-methylpropanoyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3351-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[1-(tetrahydro-2H-pyran-4-ylcarbonyl)-4piperidinyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3361-Ethyl-N-(1-propanoyl-4-piperidinyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 337N-[1-(N-Acetylglycyl)-4-piperidinyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3381-Ethyl-N-[1-(4-morpholinylacetyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3391-Ethyl-N-{1-[(4-oxocyclohexyl)carbonyl)-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3401-Ethyl-N-[1-(1-piperidinylacetyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3411-Ethyl-N-{1-[(1-methyl-5-oxo-3-pyrrolidinyl)carbonyl]4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3421-Ethyl-N-{1-[(3-methyl-3-oxetanyl)carbonyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-carboxamide 3431-Ethyl-N-{1-[(4-fluorophenyl)acetyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)1H-pyrazolo[3,4-b]pyridine-5-carboxamide 344N-{[1-(3,3-Dimethylbutanoyl)-4-piperdnyl]methylyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 345N-{[1-(Cyclopentylacetyl)-4-piperidinyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4b]pyridine-5-carboxamide 346N-{[1-(Cyclopropylcarbonyl)-4-piperidinyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3471-Ethyl-N-({1-[(4-oxocyclohexyl)carbonyl]-4-piperidinyl}methyl)-4-(tetrahyro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4b]pyridine-5-carboxamide 3481-Ethyl-N-({1-[(4-fluorophenyl)acetyl]-4-piperidinyl}methyl)-4-(tetrahydro-2H-py-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3491-Ethyl-N-({1-[(1-methyl-5-oxo-3-pyrrolidinyl)carbonyl]-4-piperidinyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide350 Methyl3-[(1-ethyl-5-{[(phenylmethyl)amino]carbonyl}-1H-pyrazolo[3,4-b]pyridin-4-yl)amino]cyclohexanecarboxylate 3513-[(1-Ethyl-5-{[(phenylmethyl)amino]carbonyl}-1H-pyrazolo[3,4-b]pyridin-4-yl)amino]cyclohexanecarboxylic acid 3521-Ethyl-N-(phenylmethyl)-4-(4-piperidinylano)1H-pyrazolo[3,4-b]pyridine-5-carboxaxnide 353 Ethyl1-ethyl-4-({1-[(methyloxy)acetyl]-4-piperidinyl}amino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 354 Ethyl1-(1-methylethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 3554-(Cyclohexylamino)-1-ethyl-N-methyl-1H-prazolo[3,4-b]pyridine-5-carboxamide3561-Ethyl-N-(4-fluorophenyl)-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3571-Ethyl-6-methyl-N-{[4-(methylsulfonyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 358N-(2,3-Dihydro-1H-inden-2-yl)-1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3601-Ethyl-N-[3-(1-piperidinylcarbonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3611-Ethyl-N-[4-(1-methylethyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3621-Ethyl-N-(2-fluorophenyl)-4-(tefrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 363N-{3-[(Dimethylamino)carbonyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 364N-{4-[(Difluoromethyl)oxy]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 365N-{4-[Acetyl(methyl)amino]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3661-Ethyl-N-(4-hydroxyphenyl)-4-(tetrahydxo-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3671-Ethyl-N-[4-(4-morpholinyl)-2-trifluoromethyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-caxboxamide 3681-Ethyl-N-4-pyridinyl-4-(tefrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3691-Ethyl-N-{4-[(4-methyl-1-piperazinyl)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3701-Ethyl-N-[2-(2-oxo-1-pyrrolidinyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3711-Ethyl-N-[3-(methylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 372N-{3-[Acetyl(methyl)amino]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3731-Ethyl-N-{3-[(methylsulfonyl)aminol]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3741-Ethyl-N-(4-fluoro-2-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 375N-(4-Chlorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 376N-(3-Chloro-2-cyanophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3771-Ethyl-N-[3-(1-piperidinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3791-Ethyl-N-[2-(methylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 380N-{2-[Acetyl(methyl)amino]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3811-Ethyl-N-[3-(4-morpholinylcarbonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 382N-(4-Chloro-3-cyanophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3831-Ethyl-N-(3-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 384N-(3-Chlorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 386N-[3-[(Acetylamino)methyl]-4-(methyloxy)phenyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3871-Ethyl-N-[4-(1-piperidinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 388N-(3-{[Cyclohexyl(methyl)amino]carbonyl}phenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3891-Ethyl-N-[2-(4-morpholinyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 390N-{3-[Acetylamino)sulfonyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolol[3,4-b]pyridine-5-carboxamide 391N-(3-Chloro-4-hydroxyphenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3921-Ethyl-N-{4-[(methylsulfonyl)amino]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3931-Ethyl-N-{3-[(methylamino)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3941-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3951-Ethyl-N-3-pyridinyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 396N-(3,4-Dichlorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 397N-[3-(Aminosulfonyl)-4-chlorophenyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3981-Ethyl-N-[3-(4-morpholinyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 3991-Ethyl-N-[4-(4-morpholinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4001-Ethyl-N-{2-[(4-methyl-1-piperazinyl)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 401N-{2-[(Dimethylamino)carbonyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 402N-{2-Chloro-4-(trifluoromethyl)phenyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Hpyrazolo[3,4-b]pyridine-5-carboxamide 403N-{2-[(Acetylamino)methyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 404N-(2-Chlorophenyl)-1-ethyl-4(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 405N-(3-Chloro-2-fluorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4061-Ethyl-N-(3-fluorophenyl)-4(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 407N-(2-Cyano-3-fluorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4081-Ethyl-N-(4-propylsulfonyl)phenyl]-4(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 409N-{4-[(Dimethylamino)carbonyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4111-Ethyl-N-[4-(methylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 413N-{4-[(Acetylamino)methyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4141-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide415N-[2-(Aminosulfonyl)ethyl]-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 416N-(2-Amino-2-oxoethyl)-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (non-preferred name) 4174-(Cyclohexylamino)-1-ethyl-N-{2-[(methylsulfonyl)amino]ethyl}-1H-pyrazolo[3,4b]pyridine-5-carboxamide 4184-(Cyclohexylamino)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4194-(Cyclohexylamino)-1-ethyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4204-(Cyclohexylamino)-1-ethyl-N-{[3-(methylsulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 421N-{[3-(Aminocarbonyl)phenyl]methyl}-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4224-(Cyclohexylamino)-1-ethyl-N-(tetrahydro-2-furanylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4234-(Cyclohexylamino)-N-({4-[(dimethylamino)sulfonyl]phenyl}methyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 424N-[(5-Chloro-2-pyridinyl)methyl]-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4254-(Cyclohexylamino)-1-ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4264-(Cyolohexylamino)-1-ethyl-N-{[6-(methyloxy)-3-pyridinyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4274-(Cyolohexylamino)-1-ethyl-N-{4-[(methylamino)carbonyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4284-(Cyclohexylamino)-1-ethyl-N-({3-[(methylamino)carbonyl]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 429N-{[4-(Aminocarbonyl)phenyl]methyl}-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4304-(Cyclohexylamimo)-1-ethyl-N-[(4-hydroxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4314-(Cyclohexylamino)-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4324-(Cyclohexylamino)-N-[(3,4-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4334-(Cyclohexylamino)-1-ethyl-N-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4344-(Cyclohexylamino)-1-ethyl-N-({3-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4354-(Cyclohexylamino)-N-[(2,5-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4364-(Cyclohexylamino)-1-ethyl-N-[(4-methylphenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4384-(Cyclohexylamino)-1-ethyl-N-(2-{4-[(methylsulfonyl)amino]phenyl}ethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4394-(Cyclohexylamino)-1-ethyl-N-[(2-hydroxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4404-(Cyclohexylanimo)-N-[(3,4-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4414-(Cyclohexylamino)-N-[(3,5-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4424-(Cyclohexylamino)-1-ethyl-N-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide4434-(Cyclohexylamino)-1-ethyl-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4444-(Cyclohexylamino)-1-ethyl-N-{[2-(methylsulfinyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4454-(Cyclohexylamino)-1-ethyl-N-[2-(4-hydroxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 446N-{2-[4-(Aminosulfonyl)phenyl]ethyl}-4-(cyclohexylanimo)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4474-(Cyclohexylamino)-1-ethyl-N-({2-[(methylamino)carbonyl]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4484-(Cyclohexylanimo)-1-ethyl-N-{[2-(methylsulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 449 Methyl2-[({[4-(cyclohexylamimo)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate 4504-(Cyclohexylamino)-1-ethyl-N-{2-[4-(methylsulfonyl)phenyl]ethyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 451N-[4,5-Bis(methyloxy)-2,3-dihydro-1H-inden-2-yl]-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4524-(Cyclohexylamino)-1-ethyl-N-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4534-(Cyclohexylamino)-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4544-(Cyclohexylamino)-1-ethyl-N-[2-(4-fluorophenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4554-(Cyolohexylamino)-1-ethyl-N-[2-(4-methylphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4564-(Cyclohexylamino)-1-ethyl-N-{2-[4-(methyloxy)phenyl]ethyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4574-(Cyclohexylamino)-1-ethyl-N-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 4584-(Cyclohexylamino)-N-[(3,5-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4594-(Cyclohexylamino)-N-(2,3-dihydro-1H-inden-1-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4604-(Cyclohexylamino)-N-{[4-(dimethylamino)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 4614-(Cyclohexylamino)-1-ethyl-N-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 462N-{[2,4-Bis(methyloxy)phenyl]methyl}-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 463N-[(6-Chloro-2-pyridinyl)methyl]-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 464N-({2-[Acetyl(methyl)amino]phenyl}methyl)-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 4654-(Cyclohexylamino)-1-ethyl-N-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl)}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4664-(Cyclohexylamino)-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4674-(Cyclohexylamino)-N-[(2,6-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 468 Methyl3-[({[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate 4694-(Cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 470 Methyl4-[({[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate 4714-(Cyclohexylamino)-1-ethyl-N-(1H-tetrazo1-5-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4724-(Cyclohexylamino)-N-({4-[(difluoromethyl)oxy]phenyl)methyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4734-(Cyclohexylamino)-1-ethyl-N-[(2-methyl-1,3-thiazo1-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 474N-[(2-Chloro-6-fluorophenyl)methyl]-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 475N-{[2-(Aminocarbonyl)phenyl]methyl}4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4774-(Cyclohexylamino)-N-{[2-(dimethylamino)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4784-(Cyclohexylamino)-1-ethyl-N-[(4-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4794-(Cyclohexylamino)-1-ethyl-N-{[3-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4804-(Cyclohexylamino)-N-[(2,6-difluorophenyl)methyl]-1-ethyl-1H-pyrazolol[3,4-b]pyridine-5-carboxamide 4814-(Cyclohexylamino)-1-ethyl-N-[(3-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4824-(Cyclohexylamino)-1-ethyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5 -carboxamide 483N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4844-(Cyclohexylamino)-1-ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4854-(Cyclohexylamino)-1-ethyl-N-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4864-(cyclohexylamino)-1-ethyl-N-[(6-oxo-1,6-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4874-(Cyclohexylamino)-1-ethyl-N-(3-pyridinylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4884-[({[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoic acid 4893-[({[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoic acid 4904-(Cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide hydrochloride 4914-(Cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide methanesulphonate 492N-({2-[(1,1-Dimethylethyl)oxy]-3-pyridinyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 493N-[(3-Chloro-4-methylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 494N-[(4-Chloro-2-methylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 495N-({2-[(Difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4961-Ethyl-N-({2-[(1-methylethyl)oxy]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4971-Ethyl-N-({3-[(1-methylethyl)oxy]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 498N-({3-[(Difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 4991-Ethyl-N-{[4-hydroxy-3-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 500N-[(5-Acetyl-2-hydroxyphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5011-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-{2-[3-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 502N-{[4-(Acetylamino)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5031-Ethyl-N-[2-(3-hydroxyphenyl)ethyl]A-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 504N-[2-(3-Chlorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5051-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(2-{4-[(trifluoromethyl)oxy]phenyl}ethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5061-Ethyl-N-{2-[3-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 507N-[2-(4-Acetylphenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 508N-[2-(3,4-Dichlorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 509N-{2-[3-(Aminosulfonyl)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 510N-{2-[3,4-Bis(methyloxy)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 512N-[2-(2,3-Dichlorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b)pyridine-5-carboxamide 513N-{2-[3,5-Bis(methyloxy)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5141-Ethyl-N-{2-[3-methyl-4-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 515N-[2-(2,6-Difluorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1Hpyrazolo[3,4-b]pyridine-5-carboxamide 516N-{2-[2,6-Bis(methyloxy)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5171-Ethyl-N-[2-(2-methylphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 518N-[(3,4-Dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 519N-[4,5-Bis(methyloxy)-2,3-dihydro-1H-inden-2-yl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 521N-{2-[4-(Aminosulfonyl)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5221-Ethyl-N-{[2-(methylsulfinyl)phenyl]methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5231-Ethyl-N-(2-phenylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 524N-{[4-(Dimethylamino)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5251-Ethyl-N-[2-(4-fluorophenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5261-Ethyl-N-[2-(4-methylphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolol[3,4-b]pyridine-5-carboxamide 527 N-{[3-(Aminosulfonyl)phenyl]methyl}-1-ethy-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5281-Ethyl-N-[(4-methylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolol[3,4-b]pyridine-5-carboxamide 5301-Ethyl-N-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 531 Methyl2-[({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate 532N-[(6-Chloro-2-pyridinyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 533N-(2,3-Dihydro-1H-inden-1-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 534N-({2-[Acetyl(methyl)amino]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 535N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 536N-[(1R)-2,3-Dihydro-1H-inden-1-yl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5371-Ethyl-N-({3-[(methylsulfonyl)amino]phenyl)methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5381-Ethyl-N-(phenylmethyl)-N-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 540N-{2-(Dimethylamino)ethyl]-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 541N-Butyl-1-ethyl-N-(-phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 542N,1-Diethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5441-Ethyl-N-(1-phenyl-4-piperidinyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5451-ethyl-N-{1-[(ethylamino)carbonyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 546 Formic acid-1-ethyl-N-[1-methyl-2-(4-methyl-1-piperazinyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (1:1) 547 Methyl[4-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)-1-piperidinyl]acetate 5481-Ethyl-N-{[4-(4-morpholinylmethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 5491-Ethyl-N-({3-[(4-methyl-1-piperazinyl)methyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolol[3,4-b]pyridine-5-carboxamide trifluoroacetate 550N-{[5-(Aminocarbonyl)-3-pyridinyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 5511-Ethyl-N-{[4-(1-methylethyl)phenyl]methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 552N-{[3-(Cyclopentyloxy)-4-(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5531-Ethyl-N-({4-[(4-methyl-1-piperazinyl)methyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 554N-[(2,4-Dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-caxboxamide 555N-[(2,4-Difluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 556N-[(2-Chloro-4-fluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 557N-{2-[2-Chloro-3-(methyloxy)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 558 Methyl3-[({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate 5591-Ethyl-N-{[3-(1-pyrrolidinylmethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoroacetate 5601-Ethyl-N-(2-{4-[(methylsulfonyl)amino]phenyl}ethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 561N-{[2,5-Bis(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 562N-{[-2,6-Bis(methyloxy)phenyl-methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5631-Ethyl-N-[(2-fluorophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 564N-[(3,5-Difluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 565N-[(4-Chlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 567N-Cyclohexyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5681-Ethyl-N-{2-[4-(methylsulfonyl)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5691-Ethyl-N-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 570N-({4-[(Cyclopropylamino)carbonyl]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5711-Ethyl-N-{[4-(4-methyl-1-piperazinyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5721-Ethyl-N-{[4-(1-pyrrolidinylmethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5731-Ethyl-N-[6-(methyloxy)-1-oxo-2,3-dihydro-1H-inden-2-yl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 574N-[(2,5-Dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 575N-[(3,5-Diethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 576N-[(2,3-Difluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5771-Ethyl-N-{[2-(methylsulfonyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5781-Ethyl-N-[(3-hydroxyphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 579N-{[3,5-Bis(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5801-Ethyl-N-[2-(4-hydroxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 581N-[(3,5-Dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 582N-{[2,4-Bis(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5831-Ethyl-N-{[2-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 584N-[(2,4-Dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5851-Ethyl-N-({2-[(methylamino)carbonyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5861-Ethyl-N-{2-[4-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 587N-[(2-Chlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5881-Ethyl-N-[(2-hydroxyphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 589N-(1,3-Benzodioxol-5-ylmethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5901-Ethyl-N-[3-(methyloxy)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 591N-(Cyclohexylmethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5921-Ethyl-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 593 Methyl4-[({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate 594N-[(3,4-Dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 595N-{[4-(Aminocarbonyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 596N-[(2,6-Difluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 597N-{[3-(Aminocarbonyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5981-Ethyl-N-[(4-hydroxyphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 5991-Ethyl-N-{[6-(methyloxy)-3-pyridinyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6001-Ethyl-N-(2-pyridinylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6011-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-{[3-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 602N-[4-(2-Amino-2-oxoethyl)phenyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6031-Ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6041-Ethyl-N-{4-[2-(methylamino)-2-oxoethyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6051-Ethyl-N-[(3-fluorophenyl)methyl]4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6061-Ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 607N-{[4-(Aminosulfonyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 608N-{[2-(Aminocarbonyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 609N-({4-[(Difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 610N-({3-[(Dimethylamino)methyl]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 611 N-{[3-Chloro-4-(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 612N-(1-Acetyl-4-piperidinyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6131-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 615N-(5-Chloro-2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 616N-({3-[Acetylamino)methyl]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6171-Ethyl-N-[(4-fluorophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6181-Ethyl-N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6191-Ethyl-N-[(2-ethylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6201-Ethyl-N-{[2-fluoro-5-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6211-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[(2,3,4-trifluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 622N-[(4-Chloro-2-fluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-IH-pyrazolo[3,4-b]pyridine-5-carboxamide 623N-[(4-Bromo-2-fluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 624N-[(3,5-Dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 625N-[(2,3-Dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 626N-[(2,3-Dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 627N-[(4-Cyanophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 628N-[(4-Bromophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6291-Ethyl-N-{[5-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6301-Ethyl-N-4-iodophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 631N-{[4-(1,1-Dimethylethyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b-pyridine-5-carboxamide 632N-[(3-Cyanophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 633N-[(2,6-Dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 634N-[(5-Chloro-2-methylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 635N-[(3,5-Dibromophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6361-Ethyl-N-[(4-ethylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6371-Ethyl-N-{[3-fluoro-4-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6381-Ethyl-N-[(2-iodophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 639N-[(2-Bromophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6401-Ethyl-N-{[4-(hydroxymethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6411-Ethyl-N-{[3-(hydroxymethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxannde 6421-Ethyl-N-{[3-(hydroxymethyl)-2-methylphenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 643N-{[2,3-Dichloro-6-(hydroxymethyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 644N-[(2,4-Dichloro-6-methylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6451-Ethyl-N-{[4-(2-methylpropyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 646N-[(2,5-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6471-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[(2,4,5-trifluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6481-Ethyl-N-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 649N-[(2-Chloro-6-methylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6504-[({[1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoic acid sodium salt 6513-[({[1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoic acid 652 Ethyl1-ethyl-4-{[4-(hydroxyimimo)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 6531-Ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 654N-{[4-(Dimethylamino)phenyl]methyl}-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6551-Ethyl-4-({4-[(ethyloxy)imino)cyclohexyl}amino)-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6561-Ethyl-4-({4-[(methyloxy)imino]cyclohexyl}amino)-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6574-[(4-{[(1,1-Dimethylethyl)oxy]imino}cyclohexyl)amino]-1-ethyl-N-([4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6581-Ethyl-N-{[4-(methyloxy)phenyl]methyl}-4-[(7-oxohexahydro-1H-azepin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 659 Ethyl1-ethyl-4-[(7-oxohexahydro-1H-azepin-4-yl)amino]-1H-pyrazolo[3,4-b]Pyridinie-5-carboxylate 6604-{[cis-4-(Butylamino)cyclohexyl]amino}-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6614-[(trans-4-Aminocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6624-[(trans-2-Aminocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6634-[(cis-2-Aminocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6644-[(3-Aminocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 665 Ethyl1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 666N,1-Diethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6671-Ethyl-N-(4-fluorophenyl)-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6681-Ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-N-(1,3-thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6691-ethyl-N-[(4-fluorophenyl)methyl]-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6701-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-N-{[4-(methylsulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide671 N-{[3,4-bis(methyloxy)phenyl]methyl}-1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6721-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-N-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6731-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 674N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 6751-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 676N-[(2,4-dimethylphenyl)methyl]-1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 667N-[(2,3-Dichlorophenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 678N-[(3-Chloro-4-methylphenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 679N-[(4-Chloro-2-methylphenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide 680N-[(2,4-Dimethylphenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide681 N-[(3,4-Dimethylphenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide682 N-[(2,3-Dichlorophenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide683 N-[(3-Chloro-4-methylphenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide684 N-[(4-Chloro-2-methylphenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide685 N-({4-[(Difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide686 1-Ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-N-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 1 Ethyl4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

That is, Example 1 is

Intermediate 1 (0.051 g) and cyclopentyl amine (0.019 g) were suspendedin ethanol (2 ml) and triethylamine (0.14 ml) was added. The mixture wasstirred under nitrogen and heated at 80° C. for 16 h. After cooling toroom temperature, ethanol was removed by evaporation under a stream ofnitrogen and the residue partitioned between dichloromethane (DCM) andwater. The layers were separated and the organic layer was loadeddirectly onto an solid phase extraction (SPE) cartridge (silica, 5 g)which was eluted sequentially with; (i) DCM, (ii) DCM: Et₂O (2:1), (iii)DCM:Et₂O (1:1), (iv) Et₂O, (v) EtOAc, (vi) MeOH. Fractions containingdesired material were combined and concentrated in vacuo to affordExample 1 (0.074 g). LCMS showed MH⁺=303; T_(RET)=3.45 min.

Similarly prepared were the following:

Amine MH⁺ T_(RET) NHR³ reagent ion (min) Example 2

Cyclohexyl amine 317 3.65 Example 3 (= Intermediate 32)

4-Amino tetrahydropyran 319 2.93 Example 5 (= Example 207*)

Intermediate 6 360 3.20*For alternative synthesis of Example 5, see Example 207 hereinafter

Example 3 (=Intermediate 32): Ethyl1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Instead of the method shown above for Examples 1-5 (called Method A),the compound of Example 3 can also be made: either using the minorvariation of Method A described in detail under “Intermediate 32”hereinabove, or using the following Method B: Example 3, Method B:Intermediate 1 (2.5 g) was dissolved in acetonitrile (15 ml).4-Aminotetrahydropyran hydrochloride (1.1 g) andN,N-diisopropylethylamine (9.4 ml) were added and the mixture stirredunder nitrogen at 85° C. for 16 h. A trace of starting materialremained, so an additional portion of 4-aminotetrahydropyranhydrochloride (0.11 g) was added and stirring continued at 85° C. for afurther 16 h. The mixture was then concentrated in vacuo. The residuewas partitioned between DCM and water. The layers were separated and theorganic layer was washed with further water (2×20 ml) then dried(Na₂SO₄) and concentrated in vacuo. The residue was further purified bychromatography using Biotage (silica, 90 g), eluting withcyclohexane:ethyl acetate to afford Example 3 (2.45 g). LCMS showedMH⁺=319; T_(RET)=2.90 min.

Example 6 Ethyl4-(cyclopentylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Intermediate 3 (0.045 g) was placed in a Reactivial™ and treated withcyclopentyl amine (0.07 ml). The mixture was heated at 90° C. for 2 h,then allowed to cool to room temperature and partitioned betweenchloroform (2 ml) and water (1 ml). The layers were separated and theorganic phase was evaporated to a brown solid, which was purified bymass directed autoprep HPLC, to afford Example 6 as a white solid (0.008g). LCMS showed MH⁺=289; T_(RET)=3.22 min.

Example 7 Ethyl1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Intermediate 3 (0.035 g) was placed in a Reactivial™ and treated with4-amino tetrahydropyran (0.06 ml). The mixture was heated at 90° C. for2 h, then allowed to cool to room temperature and partitioned betweenchloroform (2 ml) and water (1 ml). The layers were separated and theorganic phase was concentrated, then applied to a preparative TLC plate(silica, 20 cm×20 cm×1 mm) which was eluted with ethyl acetate. Therequired band was removed from the plate and the silica washed withethyl acetate (2×15 ml). Concentration of the ethyl acetate solution invacuo afforded Example 7 as a white solid (0.008 g). LCMS showedMH⁺=305; T_(RET)=2.67 min.

Example 8 Ethyl1-ethyl-4[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

that is:

Intermediate 1 (0.05 g) and (S)-(−)-3-aminotetrahydrofuran 4-toluenesulphonate (0.052 g) were suspended in ethanol (1 ml) and triethylamine(0.14 ml) was added. The mixture was stirred under nitrogen and heatedat 80° C. for 24 h. After cooling to room temperature, ethanol wasremoved by evaporation under a stream of nitrogen and the residuepartitioned between DCM (2 ml) and water (1.5 ml). The layers wereseparated and the organic layer concentrated to dryness. Purificationwas carried out using an SPE cartridge (silica, 5 g), eluting with agradient of EtOAc:cyclohexane; (1:16 then, 1:8, 1:4, 1:2, 1:1 and 1:0).Fractions containing desired material were combined and concentrated invacuo to afford Example 8 (0.052 g). LCMS showed MH⁺=305; T_(RET)=2.70min.

Similarly prepared were the following:

Amine NHR³ Reagent MH⁺ion T_(RET)(min) Example 9

(R)-(+)-3- Aminotetra- hydrofuran 4-toluene- sulphonate 305 2.73 Example10

Intermediate 11 335 3.21 Example 11 (mixture of enantiomers)

Intermediate 12 321 3.10 Example 12

Cyclopropyl amine 275 2.98

Example 13 Ethyl4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Intermediate 1 (0.05 g) and Intermediate 13 (0.027 g) were suspended inethanol (1 ml) and triethylamine (0.14 ml) was added. The mixture wasstirred under nitrogen and heated at 80° C. for 24 h. After cooling toroom temperature, ethanol was removed by evaporation under a stream ofnitrogen and the residue partitioned between DCM (2 ml) and water (1.5ml). The layers were separated and the organic layer concentrated todryness. Purification was carried out using an SPE cartridge (silica, 5g), eluting with a gradient of EtOAc:cyclohexane; (1:8 then 1:4, 1:2,1:1 and 1:0). Fractions containing desired material were combined andconcentrated in vacuo to afford Example 13 (0.045 g) as a mixture ofenantiomers. LCMS showed MH⁺=353; T_(RET)=2.60 min.

Similarly prepared was the following:

Amine NHR³ Reagent MH⁺ion T_(RET)(min) Example 14

Intermediate 14 367 2.64

Example 19 (Reference Examples as an Intermediate): Ethyl4-(cyclopentylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Intermediate 2 (0.035 g) was placed in a Reactivial™ and treated withcyclopentyl amine (0.05 ml). The mixture was heated at 90° C. for 1.5 h,then allowed to cool to room temperature and partitioned betweenchloroform (2 ml) and water (1 ml). The layers were separated and theorganic phase was concentrated. The residual solid was triturated withEt₂O and the insoluble off-white solid collected and air-dried to affordExample 19 (0.016 g). LCMS showed MH⁺=275; T_(RET)=2.58 min.

Example 20 (Reference Example, as an Intermediate): Ethyl4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

that is:

Intermediate 2 (0.035 g) was placed in a Reactivial™ and treated with4-aminotetrahydropyran (0.05 ml). The mixture was heated at 90° C. for1.5 h, then allowed to cool to room temperature and partitioned betweenchloroform (2 ml) and water (1 ml). The layers were separated and theorganic phase was concentrated. The crude product was purified by massdirected autoprep HPLC to afford Example 20 as an off-white solid (0.011g). LCMS showed MH⁺=291; T_(RET)=2.08 min.

Alternative Synthetic Method for Example 20:

Intermediate 2 (2 g) was suspended in 4-aminotetrahydropyran (2 g), andthe mixture was heated at 90° C. for 6 h. The residual mixture wasallowed to cool to room temperature and partitioned between chloroform(50 ml) and water (50 ml). The phases were separated and the organicphase was evaporated to dryness. The residue was triturated with Et₂O(30 ml) and the insoluble solid was collected and dried to affordExample 20 as a cream solid (2.24 g). LCMS showed MH⁺=291; T_(RET)=2.19min.

Example 21 N-benzyl-1-ethyl-4-(tetrahydro-2H-pyran4-ylamino)-1-pyrazolo[3,4-b]pyridine-5-carboxamide

that is, Example 21 is:

Three alternative methods, A, B and C, have been used to make Example21, as follows:

Example 21 Method A

A solution of the 4-chloro Intermediate 17 (0.031 g, 0.1 mmol) inethanol (1.9 ml) was treated with triethylamine (0.07 ml, 0.5 mmol),followed by a 0.1M ethanolic solution of 4-aminotetrahydropyran(Intermediate 8, 1.1 ml of the 0.1M ethanolic solution=0.11 mmol). Themixture was heated at reflux (80° C.) for 18 h. A further portion of4-amino-tetrahydropyran (0.01 ml of undiluted amine, not a solutionthereof) was then added and heating continued for a further 24 h.Volatiles were removed in vacuo and the residue dissolved indichloromethane (DCM), then applied to an solid phase extraction (SPE)cartridge (aminopropyl, 1 g) which was eluted first with DCM, then withmethanol. Fractions containing desired material were concentrated invacuo to afford Example 21 (0.004 g). LCMS showed MH⁺=380; T_(RET)=2.92min.

Example 21 Method B

Intermediate 17 (0.031 g, 0.1 mmol) was dissolved in acetonitrile (1ml). 4-Aminotetrahydropyran hydrochloride (Intermediate 8A, 0.015 g,0.11 mmol) and N,N-diisopropylethylamine (0.08 ml, 0.5 mmol) were addedand the mixture stirred under nitrogen at 85° C. for 16 h, thenconcentrated in vacuo. The residue was partitioned betweendichloromethane (DCM) and water. The layers were separated and theorganic layer was concentrated in vacuo to afford Example 21 (0.027 g).LCMS showed MH⁺=380; T_(RET)=2.92 min.

Example 21 Method C

This alternative route C to Example 21 involves formation of the esterof Example 3 Intermediate 32

using one of the methods described above, conversion of the ester ofExample 3/Intermediate 32 into the carboxylic acid (Intermediate 33)using the method given above for Intermediate 33, and then amide bondformation to form Example 21 using the method of Examples 81-84 below.

The following compounds can be similarly prepared using one or more ofMethods A, B or C above, preferably Method A or B:

Starting Material NR⁴R⁵ NHR³ (for Method A or B) Amine Reagent MH⁺ ionT_(RET) (min) Example 22

Intermediate 19 4-amino tetrahydropyran 384 3.09 Example 23

Intermediate 20 Cyclopentyl amine 342 3.29 Example 24

Intermediate 20 Cyclohexyl amine 356 3.47 Example 25

Intermediate 20 4-amino tetrahydropyran 358 2.79 Example 27

Intermediate 20 Intermediate 6 400 2.64 Example 28

Intermediate 21 Cyclopentyl amine 328 2.68 Example 29

Intermediate 21 Cyclohexyl amine 342 2.87 Example 30

Intermediate 21 4-amino tetrahydropyran 344 2.33 Example 31

Intermediate 22 Cyclopentyl amine 365 2.38 Example 32

Intermediate 22 Cyclohexyl amine 379 2.54 Example 33

Intermediate 22 4-amino tetrahydropyran 381 2.09 Example 34 NH₂

Intermediate 24 Cyclopentyl amine 274 2.59 Example 35 NH₂

Intermediate 24 Cyclohexyl amine 288 2.79 Example 36 NH₂

Intermediate 24 4-amino tetrahydropyran 290 2.22

Example 39N-Benzyl-4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

that is, Example 39 is:

A solution of Intermediate 17 (0.031 g, 0.1 mmol) in ethanol (1 ml) wastreated with triethylamine (0.07 ml, 0.5 mmol), followed by a 0.1Methanolic solution of cyclopentyl amine (1.1 ml of the 0.1M ethanolicsolution=0.11 mmol). The mixture was heated at reflux (80° C.) for 18 h.A further portion of cyclopentyl amine (0.009 ml of undiluted amine, nota solution thereof) was then added and heating continued for a further24 h. Volatiles were removed in vacuo and the residue dissolved in DCM,then applied to an SPE cartridge (aminopropyl, 1 g) which was elutedfirst with DCM, then with methanol. The DCM fraction was concentrated invacuo, then applied to an SPE cartridge (silica, 0.5 g) which was elutedsequentially with (i) DCM, (ii) Et₂O, (iii) EtOAc and (iv) MeOH.Fractions containing desired material were combined to afford Example 39(0.007 g). LCMS showed MH⁺=364; T_(RET)=3.38 min.

Similarly prepared were the following:

Starting Amine MH⁺ T_(RET) NR⁴R⁵ NHR³ Material reagent ion (min) Example40

Intermediate 17 Cyclohexyl amine 378 3.43 Example 41

Intermediate 17 Intermediate 6 421 2.75 Example 42

Intermediate 18 Cyclopentyl amine 358 3.63 Example 43

Intermediate 18 Cyclohexyl amine 372 3.79 Example 44

Intermediate 18 4-amino tetrahydro- pyran 378 3.13 Example 45

Intermediate 18 Intermediate 7 378 2.37 Example 46

Intermediate 18 Intermediate 6 415 2.92 Example 47

Intermediate 19 Cyclopentyl amine 368 3.61 Example 48

Intermediate 19 Cyclohexyl amine 382 3.76 Example 49

Intermediate 19 Intermediate 7 397 2.29 Example 50

Intermediate 19 Intermediate 6 425 2.88 Example 51

Intermediate 23 Cyclopentyl amine 316 3.05 Example 52

Intermediate 23 Cyclohexyl amine 330 3.26 Example 53

Intermediate 23 4-amino tetrahydro- pyran 332 2.58 Example 55

Intermediate 23 Intermediate 6 373 2.46

Example 574-[(1-Acetylpiperidin-4-yl)amino]-1-ethyl-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

that is, Example 57 is:

A solution of Intermediate 22 (0.03 g, ca. 0.1 mmol) in ethanol (1 ml)was treated with triethylamine (0.07 ml, 0.5 mmol), followed by a 0.1Methanolic solution of Intermediate 6 (1.1 ml of the solution=0.11 mmol).The mixture was heated at reflux (80° C.) for 18 h. A further portion ofIntermediate 6 (0.01 ml, undiluted) was then added and heating continuedfor a further 24 h. Volatiles were removed in vacuo and the residuedissolved in DCM, then applied to an SPE cartridge (aminopropyl, 1 g)which was eluted first with DCM, then with methanol.

The DCM fraction was concentrated in vacuo, then applied to an SPEcartridge (silica, 0.5 g) eluting with (I) DCM, (ii) EtOAc and (iii) astepwise gradient of chloroform:methanol (from 99:1 up to 4:1).Fractions containing desired material were combined to afford Example 57(0.003 g). LCMS showed MH⁺=422; T_(RET)=2.1 min.

Example 61N-Benzyl-4-(cyclopentylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A solution of Intermediate 28 (0.03 g, 0.1 mmol) in ethanol (1 ml) wastreated with a 0.1M ethanolic solution of cyclopentyl amine (1.1 ml ofsolution=0.11 mmol). Triethylamine (0.07 ml, 0.5 mmol) was then addedand the mixture heated at reflux (85° C.), under nitrogen for 12 h. Afurther portion of cyclopentyl amine (0.009 ml, undiluted) was thenadded and heating continued for a further 36 h. The mixtures wereconcentrated in vacuo and the residue treated with chloroform. A smallamount of insoluble material was collected by filtration, then thefiltrate applied to an SPE cartridge (aminopropyl, 1 g) which was elutedfirst with DCM, then with methanol. Fractions containing desiredmaterial were combined to afford Example 61 (0.039 g). LCMS showedMH⁺=350; T_(RET)=2.88 min.

Similarly prepared were the following:

Starting Amine MH⁺ T_(RET) NR⁴R⁵ NHR³ Material reagent ion (min) Example62

Intermediate 28 Cyclohexyl amine 364 3.05 Example 63

Intermediate 28 4-amino tetrahydropyran 366 2.52 Example 64

Intermediate 30 Cyclopentyl amine 344 3.06 Example 65

Intermediate 30 Cyclohexyl amine 358 3.23 Example 66

Intermediate 30 4-amino tetrahydropyran 360 2.69 Example 67

Intermediate 29 Cyclopentyl amine 354 3.17 Example 68

Intermediate 29 Cyclohexyl amine 368 3.33 Example 69

Intermediate 29 4-amino tetrahydropyran 370 2.72 Example 70 NH₂

Intermediate 31 Cyclopentyl amine 260 2.10 Example 71 NH₂

Intermediate 31 Cyclohexyl amine 274 2.29

Example 744-[(1-Acetylpiperidin-4-yl)amino]-N-benzyl-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

that is, Example 74 is:

A solution of Intermediate 28 (0.03 g, 0.1 mmol) in ethanol (1 ml) wastreated with a 0.1M ethanolic solution of Intermediate 6 (1.1 ml ofsolution=0.11 mmol). Triethylamine (0.07 ml, 0.5 mmol) was then addedand the mixture heated at reflux (85° C.), under nitrogen for 12 h. Afurther portion of Intermediate 6 (0.1 mmol) was then added and heatingcontinued for a further 36 h. The mixtures were concentrated in vacuoand the residue treated with chloroform. A small amount of insolublematerial was collected by filtration, then the filtrate applied to anSPE cartridge (aminopropyl, 1 g) which was eluted first with DCM, thenwith methanol. Fractions containing desired material were combined andconcentrated in vacuo. The residue was further purified by SPE (silica,0.5 g) eluting with (i) DCM, (ii) chloroform, (iii) EtOAc and (iv) astepwise gradient of chloroform:methanol (from 99:1 up to 4:1).Fractions containing desired material were combined to afford Example 74(0.029 g). LCMS showed MH⁺=407; T_(RET)=2.57 min.

Example 811-Ethyl-N-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

To a stirred suspension of Intermediate 33 (0.025 g, ca. 0.08 to 0.09mmol) in chloroform (2 ml) was added thionyl chloride (0.025 ml) and themixture stirred at room temperature for 1 h. The mixture was cooled to0° C. and methylamine added (2M solution in THF, 0.69 ml=1.38 mmol).After returning to room temperature the mixture was stirred for afurther 1 h, then quenched by addition of water (4 ml) and the layersseparated. The organic layer was concentrated then applied to an SPEcartridge (silica, 1 g) which was eluted with (i) DCM, (ii) Et₂O (2:1),(iii) EtOAc, (iv) MeOH: EtOAc (1:9). Fractions containing desiredmaterial were combined to afford Example 81 (0.019 g). LCMS showedMH⁺=304; T_(RET)=2.19 min.

Similarly prepared:

MH⁺ T_(RET) NR⁴R⁵ Amine reagent ion (min) Example NMe₂ Dimethylamine (2Min THF) 318 2.06 82 Example NHEt Ethylamine (2M in THF) 318 2.31 83Example NH^(i)Pr Isopropylamine (2M in THF) 332 2.44 84

Example 83N,1-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;also named1-ethyl-N-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

In an alternative embodiment to the process described for Examples 81-84above, Example 83 can be made according to the following method:

A mixture of Intermediate 33 (3.0 g, 10.33 mmol), EDC (2.25 g, 11.7mmol), and HOBT (1.68 g, 12.4 mmol) was stirred at room temperature for1 hour. Ethylamine (6.2 ml, 12.4 mmol, 2M-solution in THF) was added,and stirring was continued at room temperature for 22 hours. Thesolvents were removed in vacuo, and the residual solid was dissolved inchloroform (250 ml) and washed successively with water (70 ml) and5%-sodium hydrogen carbonate solution (70 ml). After drying overanhydrous sodium sulphate, the organic solution was evaporated in vacuoto give a pale orange solid (4.15 g). This solid was dissolved in amixture of dichloromethane (5 ml) and chloroform (5 ml) and purifiedby-column chromatography (Biotage, silica, 100 g), eluting initiallywith EtOAc-cyclohexane (2:1) and finally with neat EtOAc. The productcontaining fractions were combined and evaporated to give Example 83 asa pale yellow solid (3.05 g). LCMS showed MH⁺=318; T_(RET)=2.33 min. ¹HNMR (400 MHz in d₆-DMSO, 27° C., δppm) 9.76 (d, 1H) 8.35 (s, 1H) 7.94(s, 1H) 5.99 (br m, 1H) 4.47 (q, 2H) 4.16-4.01 (m's, 3H) 3.62 (m, 2H)3.48 (m, 2H) 2.13 (m, 2H) 1.77 (m, 2H) 1.49 (t, 3H) 1.28 (t, 3H).

Example 85N-Benzyl-1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

That is, Example 85 is:

Intermediate 41 (0.017 g, 0.062 mmol) was dissolved in DMF (2 ml), thentreated with HATU (0.023 g) followed by diisopropylethyl amine (0.021ml) and the mixture stirred for 10 min. Benzylamine (0.007 ml) was thenadded and stirring continued for a further 64 h. The mixture wasconcentrated in vacuo and the residue dissolved in DCM (1.5 ml) thentreated with saturated aqueous sodium bicarbonate solution (1.5 ml).This mixture was stirred for 30 min, then the layers were separated andthe organic layer was applied to an SPE cartridge (silica, 1 g) whichwas eluted sequentially with a gradient of ethyl acetate: cyclohexane(1:4, then 1:2, 1:1, 2:1 and 1:0). Fractions containing desired materialwere concentrated in vacuo to afford Example 85 (0.017 g). LCMS showedMH⁺=366; T_(RET)=2.80 min.

Similarly prepared were the following:

Starting T_(RET) NHR³ material MH⁺ ion (min) Example 86

Intermediate 42 366 2.80 Example 87

Intermediate 44 382 3.11 Example 88

Intermediate 45 336 3.00 Example 89

Intermediate 46 414 2.69 Example 90

Intermediate 47 428 2.75

Example 91N-Benzyl-1-ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Intermediate 43 (0.019 g) was dissolved in DMF (2 ml), then treated withHATU (0.024 g) followed by diisopropylethyl amine (0.022 ml) and themixture stirred for 10 min. Benzylamine (0.007 ml) was then added andstirring continued for a further 64 h. The mixture was concentrated invacuo and the residue dissolved in DCM (1.5 ml) then treated withsaturated aqueous sodium bicarbonate solution (1.5 ml). This mixture wasstirred for 30 min, then the layers were separated and the organic layerapplied to an SPE cartridge (silica, 1 g) which was eluted sequentiallywith a gradient of ethyl acetate: cyclohexane (1:4, then 1:2, 1:1 and1:0). Fractions containing desired material were concentrated in vacuoto afford Example 91 (0.023 g). LCMS showed MH⁺=396; T_(RET)=3.26 min.

Example 921-Ethyl-N-(4-fluorophenyl)-4-[(3S)tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

that is, Example 92 is:

Intermediate 41 (0.017 g) was dissolved in DMF (2 ml), then treated withHATU (0.023 g) followed by diisopropylethyl amine (0.021 ml) and themixture stirred for 10 min. 4-Fluoroaniline (0.006 ml) was then addedand stirring continued for a further 64 h. The mixture was concentratedin vacuo and the residue dissolved in DCM (1.5 ml) then treated withsaturated aqueous sodium bicarbonate solution (1.5 ml). This mixture wasstirred for 30 min, then the layers were separated and the organic layerconcentrated in vacuo. The crude mixture was purified by mass directedautoprep HPLC to afford Example 92 (0.013 g). LCMS showed MH⁺=370;T_(RET)=2.91 min.

Similarly prepared were the following:

Starting T_(RET) NHR³ material MH⁺ ion (min) Example 93

Intermediate 42 370 2.91 Example 94

Intermediate 43 400 3.37 Example 95

Intermediate 44 386 3.27 Example 96

Intermediate 45 340 3.21 Example 97

Intermediate 46 418 2.80 Example 98

Intermediate 47 432 2.84

Example 99

In all of Examples 22 to 98, where a 4-amino 5-carboxamide Example ofthe following Formula I has been synthesised from the 4-chloroderivative, then an alternative final-step synthesis is as follows:

An intermediate of Formula IV above (0.1 mmol) was dissolved inacetonitrile (1 ml). An amine of formula R³NH₂ (0.11 mmol, 1.1 moleequivalents) and N,N-diisopropylethylamine (0.5 mmol, 5 moleequivalents) were added and the mixture stirred under nitrogen at 85° C.for 16 h. After concentration in vacuo, the residue was partitionedbetween dichloromethane (DCM) and water. The layers were separated andthe organic layer was concentrated in vacuo to afford an Example ofFormula I.

Example 100

Intermediate 33 (0.048 mmol) was dissolved in DMF (0.5 ml), then treatedwith HATU (0.048 mmol) followed by diisopropylethyl amine (0.096 mmol)and the mixture stirred for 10 min. 4-Methylsulfonylbenzylamine (0.052mmol, available from Acros Organics) was then added and stirringcontinued for a further 16 hours. The mixture was concentrated in vacuo.The crude mixture was purified by mass directed autoprep HPLC to affordExample 100 (0.013 g). LCMS showed MH⁺=458; T_(RET)=2.22 min.

Similarly prepared, but replacing the 4-methylsulfonylbenzylamine withthe same or similar number of moles of another amine R⁴R⁵NH, were thefollowing compounds (Examples 102 to 182):

NR⁴R⁵ (the N atom linking R⁴ and R⁵ to the Starting —CO-pyrazolopyridinemoiety is underlined) Source of R⁴R⁵NH Material MH⁺ ion T_(RET) (min)Example 102

J. Chem. Soc., 1945, 633 Intermediate 33 458 2.2 Example 103

WO 98/52943 Intermediate 33 490 2.66 Example 104

J. Org. Chem., 1979, 44(3), 396 Intermediate 33 415 2.28 Example 105

Seriya Khimicheskaya, 1989, (7), 1694 Intermediate 33 456 2.65 Example106

SALOR (Aldrich) Intermediate 33 458 2.32 Example 107

Maybridge Chemical Company Ltd. Trevillett Tintagel Cornwall PL34 0HWUnited Kingdom Intermediate 33 461 2.5 Example 108

MicroChemistry- RadPharma Shosse Entusaistov 56 Moscow, 111123 RussiaIntermediate 33 390 2.28 Example 109

MicroChemistry- RadPharma Shosse Entusaistov 56 Moscow, 111123 Russia.Alternatively, available from: Matrix Scientific (USA), or Synthesis1998, 641, or Tetra- hedron 1995, 51, 12731 Intermediate 33 387 2.13Example 110

Bulletin des Societes Chimiques Belges, (1982), 91(2), 1953 Intermediate33 382 1.98 Example 111

MicroChemistry- RadPharma Shosse Entusaistov 56 Moscow, 111123 RussiaIntermediate 33 401 2.14 Example 112

Intermediate 33 466 2.67 Example 113

Ultrafine (UFC Ltd.), see above for address Intermediate 33 425 2Example 114

Austin Chemical Company Inc. 1565 Barclay Blvd. Buffalo Grove, IL, 60089USA Intermediate 33 382 2 Example 115

WO 02/83624 Intermediate 33 464 1.97 Example 116

Fluka Chemie AG Intermediate 33 432 2.52 Example 117

MicroChemistry- RadPharma Shosse Entusaistov 56 Moscow, 111123 RussiaIntermediate 33 397 1.96 Example 118

WO 02/85860 Intermediate 33 423 2.09 Example 119

Butt Park Ltd. Braysdown Works Peasedown St John Bath, BA2 8LL, UnitedKingdom Intermediate 33 423 2.19 Example 120

Sigma Intermediate 33 398 1.77 Example 121

US 4562184 Intermediate 33 452 2.21 Example 122

Dynamit Nobel GmbH, Germany; or Saville Whittle Ltd (UK agents ofDynamit Nobel), Vickers Street, Manchester M40 8EF, United KingdomIntermediate 33 372 1.93 Example 123

WO 02/66470 Intermediate 33 385 1.93 Example 125

Aldrich Intermediate 33 434 2.84 Example 126

AstaTech, Inc. 8301 Torresdale Ave. 19C, Philadelphia, PA 19136, USAIntermediate 33 473 2.5 Example 127

Intermediate 33 425 1.99 Example 128

J. Org. Chem., 2001, 66(6), 1999 Intermediate 33 423 1.97 Example 129

Acros Organics Intermediate 33 401 1.82 Example 130

Aldrich Intermediate 33 374 2.08 Example 131

Combi-Blocks Inc., 7949 Silverton Av., Suite 915, San Diego CA 92126,USA (see also Intermediate 8A) Intermediate 33 374 2.04 Example 132

J. Org. Chem., 1955, 20, 1657 Intermediate 33 487 2.39 Example 133

J. Med. Chem., 1999, 42(14), 2504; or variation of: Lis et al., J. Med.Chem., 1990, 33(10), 2883, see Scheme III and ref. 24 Intermediate 33473 2.24 Example 135

Aldrich Intermediate 33 396 2.42 Example 136

Aldrich Intermediate 33 415 2.03 Example 137

Aldrich Intermediate 33 401 1.78 Example 138

Aldrich Intermediate 33 381 1.81 Example 139

MicroChemistry- RadPharma Shosse Entusaistov 56 Moscow, 111123 RussiaIntermediate 33 387 1.74 Example 140

Aldrich Intermediate 33 360 2.16 Example 141

Aldrich Intermediate 33 401 1.81 Example 142

Aldrich Intermediate 33 417 1.75 Example 143

Aldrich Intermediate 33 376 2.16 Example 144

Aldrich; or Baruah et al., Synlett, 1999, 4, 409 Intermediate 33 3862.59 Example 145

Aldrich Intermediate 33 375 1.73 Example 146

Fluorochem Ltd. Wesley Street Old Glossop Derbyshire SK13 7RY UnitedKingdom Intermediate 33 360 2.16 Example 147

Aldrich; or Acros; or Jung et al., Tetrahedron Lett., 2002, 43(48),8735; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; or OrganicLett., 2002, 4(12), 2055 Intermediate 33 410 2.4 Example 148

Berk Univar plc Berk House P.O. Box 56 Basing View Basingstoke HantsRG21 2E6, United Kingdom Intermediate 33 473 2.26 Example 149

Aldrich Intermediate 33 375 1.9 Example 150

MicroChemistry- RadPharma Shosse Entusaistov 56 Moscow, 111123 RussiaIntermediate 33 411 1.95 Example 152

Nippon Kagaku Zasshi., 1960, 81 p. 962. Intermediate 33 453 1.96 Example153

Aldrich Intermediate 33 408 2.35 Example 154

Aldrich Intermediate 33 416 2.5 Example 155

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; or OrganicLetters, 2002, 4(12), 2055 Intermediate 33 448 2.68 Example 156

Alfa Aesar, A Johnson Matthey Company 30 Bond Street Ward Hill, MA01835-8099 USA Intermediate 33 360 2.16 Example 157

Aldrich Intermediate 33 330 2.04 Example 158

Aldrich Intermediate 33 347 1.83 Example 159

Aldrich Intermediate 33 396 2.49 Example 160

Aldrich Intermediate 33 416 2.53 Example 161

Aldrich Intermediate 33 390 2.18 Example 162

Aldrich Intermediate 33 463 1.96 Example 163

US 4987132 Intermediate 33 458 2.13 Example 164

Aldrich Intermediate 33 374 2.22 Example 165

Aldrich; or TCI- America; or Maybridge-Int. Intermediate 33 406 2.53Example 166

Maybridge Chemical Company Ltd. Trevillett Tintagel Cornwall PL34 0HWUnited Kingdom Intermediate 33 402 1.93 Example 167

Aldrich; or Baruah et al., Synlett, 1999, 4, 409 Intermediate 33 440 2.3Example 168

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; or OrganicLetters, 2002, 4(12), 2055 Intermediate 33 414 2.58 Example 169

Aldrich Intermediate 33 373 1.64 Example 170

Aldrich Intermediate 33 334 1.85 Example 171

Aldrich Intermediate 33 465 2.29 Example 172

EP 666258 Intermediate 33 458 2.25 Example 173

J. Chem. Soc., 1954, 1171 Intermediate 33 389 1.98 Example 174

Peakdale Molecular Ltd, Peakdale Science Park, Sheffield Road,Chapel-en-le-Frith, High Peak SK23 0PG, United Kingdom Intermediate 33459 2.36 Example 175

Fluorochem Ltd. Wesley Street Old Glossop Derbyshire SK13 7RY UnitedKingdom Intermediate 33 459 2.36 Example 176

Lancaster Synthesis Ltd, Newgate, White Lund, Morecambe, Lancashire LA33DY, United Kingdom Intermediate 33 343 2.01 Example 178

TimTec, Inc. P O Box 8941 Newark, DE, 19714- 8941 USA Intermediate 33384 2.03 Example 179

ChemBridge Europe, 4 Clark's Hill Rise, Hampton Wood, Evesham,Worcestershire WR11 6FW, United Kingdom Intermediate 33 398 1.70 Example180

Aldrich Intermediate 33 400 2.41 Example 181

Aldrich Intermediate 33 428 2.61 Example 182

Aldrich Intermediate 33 424 2.49

Example 1091-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(1,3-thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

An alternative process for preparing Example 109 is given below:1-Hydroxybenzotriazole (0.215 g, 1.59 mmol) and1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (0.357 g,1.86 mmol) were added to a suspension of Intermediate 33 (0.384 g, 1.32mmol) in DMF (10 ml). After stirring at room temperature for 30 minutes,(1,3-thiazol-2-ylmethyl)amine (0.182 g, 1.59 mmol) (commerciallyavailable from MicroChemistry Building Blocks (Russia) or MatrixScientific (USA), or preparable as disclosed in Synthesis 1998, 641, orTetrahedron 1995, 51, 12731) was added. The reaction was stirred for 18hours and then partitioned between ether and water. The organic phasewas washed with brine, dried (MgSO₄) and evaporated in vacuo. Theresidue was purified by chromatography (Biotage, silica 90 g) elutingwith cyclohexane: EtOAc followed by EtOAc. The material was trituratedwith cyclohexane and filtered to afford Example 109 (0.244 g) as a paleyellow solid. LCMS showed MH⁺ 387; T_(RET)=2.49 min. ¹H NMR (400 MHz inCDCl₃, 8 ppm) δ 9.74 (d, 1H) 8.50 (s, 1H) 7.94 (s, 1H) 7.74 (d, 1H),7.33 (d, 1H), 7.17 (m, 1H), 4.94 (d, 2H) 4.45 (q, 2H) 4.15-4.00 (m, 3H),3.63 (m, 2H), 2.15 (m, 2H) 1.85-1.73 (m, 3H) 1.48 (t, 3H).

Example 167N-{[3,4-Bis(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

In an alternative embodiment to the process described above for Examples100-182, Example 167 can be made according to the following method:

A mixture of Intermediate 33 (0.498 g, 1.72 mmol), EDC (0.46 g, 2.41mmol), and HOBT (0.278 g, 1.68 mmol) was stirred at room temperature for0.25 hours. Veratrylamine (3,4-dimethoxybenzylamine, 0.31 ml, 2.05 mmol,obtainable from Aldrich or Synlett, 1999, 4, 409) was added, andstirring was continued at room temperature for 22 hours. The reactionmixture was partitioned between Et₂O and water. The aqueous phase wasextracted with Et₂O and the combined organic phases washed with brine,dried (MgSO₄) and evaporated in vacuo. The residue was purified bychromatography (Biotage, silica 40 g) eluting with EtOAc: cyclohexane(2:1). The material was further purified by SPE (SCX-2, 10 g) elutingwith methanol then ammonia in methanol (0.5M). The ammonia methanolfractions were combined and evaporated in vacuo to afford Example 167 asa white foam (0.633 g). LCMS showed MH⁺=440; T_(RET)=2.65 min. ¹H NMR(400 MHz in CDCl₃, 27° C., δppm) 9.78 (d, 1H) 8.37 (s, 1H) 7.94 (s, 1H)6.94-6.82 (m, 3H) 6.29 (br m, 1H) 4.56 (d, 2H) 4.46 (q, 2H) 4.15-4.01(m's, 3H) 3.89 (s, 6H) 3.63 (m, 2H) 2.15 (m, 2H) 1.78 (m, 2H) 1.49 (t,3H).

Example 1781-Ethyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

The ¹H NMR data for Example 178 (as prepared by the process described inExamples 100-182 above) was as follows:

¹H NMR (400 MHz in CDCl₃, δppm) δ 9.90 (m, 1H) 8.37 (s, 1H) 7.94 (s, 1H)7.49 (s, 1H), 7.40 (s, 1H) 6.39 (m, 1H) 4.50-4.42 (m, 41) 4.15-4.00 (m,3H) 3.89 (s, 3H), 3.63 (m, 21) 2.52 (m, 2H) 2.20-2.10 (m, 2H) 1.85-1.73(m, 3H) 1.48 (t, 3H).

Example 183 Ethyl4-(cyclohexylamino)-1-(3-ethoxy-3-oxopropyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A vigorously stirred mixture of Intermediate 48 (40 mg), anhydrouspotassium carbonate (57 mg) and ethyl 3-bromopropanoate (0.027 ml) inanhydrous DMF (1 ml) was heated at 65° C. overnight. The reactionmixture was concentrated, and the residue was partitioned betweendichloromethane (5 ml) and water (5 ml). The phases were separated andthe organic phase was evaporated to a residual oil which was purified bymass directed autoprep HPLC to afford Example 183 (5 mg). LCMS showedMH⁺=389; T_(RET)=3.65 min.

Example 185 Ethyl1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Sodium hydride (0.067 g, 60% dispersion in oil) was added to a stirredsolution of Example 20 (0.47 g) in DMF (19 ml), followed by n-propyliodide (0.17 ml). The mixture was stirred at 23° C. for 16 hours, thenconcentrated, diluted with chloroform (30 ml) and washed with 1:1water:brine solution (30 ml), separated and the organic layerconcentrated. The residue was purified on a SPE catridge (silica, 10 g)eluting with 10 ml volumes of dichloromethane, 1:1 diethylether:cyclohexane, and diethyl ether. The combined 1:1 diethyl ether:cyclohexane, and diethyl ether, fractions were concentrated to giveExample 185 as a clear gum (0.23 g). LCMS showed MH⁺=333; T_(RET)=3.14min.

Example 186 Ethyl1-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

2-Bromoethanol (0.008 ml) was added to a solution of Example 20 (0.03 g)in anhydrous DMF (1.5 ml), with2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine(polymer bound, 2.3 mmol/g loading, 0.045 g). The mixture was shaken at23° C. for 16 hours, then the solution drained from the resin, and theresin was washed with DMF. The combined organics were concentrated, andthe residue purified on a SPE cartridge (silica, 1 g) eluting with70-100% ethyl acetate in cyclohexane. The combined fractions wereconcentrated to give Example 186 as a white solid (0.011 g). LCMS showedMH⁺=335; T_(RET)=2.47 min.

Example 187N-[4-(Methylsulfonyl)benzyl]-1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Intermediate 50 (0.03 g) was stirred in DMF (1 ml) with DIPEA (0.035 ml)and HATU (0.038 g) for 20 min. 4-(Methylsulfonyl)benzylaminehydrochloride (0.024 g) was added to the mixture and the solution wasstirred for 8 hours at 23° C. The solution was concentrated and theresidue dissolved in dichloromethane (6 ml) then washed with saturatedsodium bicarbonate solution (6 ml) and 1:1 brine:water (6 ml), separatedby hydrophobic frit. The organic layer was concentrated to give Example187 as a white solid (0.039 g). LCMS showed MH⁺=472; T_(RET)=2.67 min.

Example 188N-(4-Fluorophenyl)-1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

The synthetic method is as described in Example 187, except that inplace of 4-(methylsulfonyl)benzylamine hydrochloride, 4-fluoroaniline(0.01 ml) was added to the mixture. The resultant product requiredfurther purification, which was performed by mass directed autoprepHPLC, giving Example 188 as a clear gum (0.03 g). LCMS showed MH⁺=398;T_(RET)=3.13 min.

Example 189 Ethyl1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

4-Aminotetrahydropyran hydrochloride (Intermediate 8A, 0.413 g, 3.0mmol) was added to a mixture of Intermediate 51 (0.268 g, 11.0 mmol) andN,N-diisopropylethylamine (0.87 ml, 5.0 mmol) in acetonitrile (3 ml).The resulting mixture was heated at 85° C. for 24 hours. Volatiles wereremoved in vacuo and the residue was dissolved in chloroform (1.5 ml)and applied to a SPE cartridge (silica, 5 g). The cartridge was elutedsuccessively with Et₂O, EtOAc and EtOAc-MeOH (9/1). Fractions containingthe desired product were combined and concentrated in vacuo to give thedesired product contaminated with starting material (Intermediate 51).Further purification using a SPE cartridge (silica, 5 g) eluting withethyl acetate-cyclohexane (1/3) afforded Example 189 (0.248 g). LCMSshowed MH⁺=333; T_(RET)=2.75 min.

Example 190 Ethyl4-(cyclohexylamino)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Cyclohexylamine (0.149 g, 1.5 mmol) was added to a mixture ofIntermediate 51 (0.201 g, 0.75 mmol) and N,N-diisopropylethylamine (0.65ml, 3.73 mmol) in acetonitrile (3 ml). The resulting mixture was heatedat 85° C. for 40 hours. Volatiles were removed in vacuo and the residuewas dissolved in chloroform (1.5 ml) and applied to a SPE cartridge(silica, 5 g). The cartridge was eluted successively with Et₂O, EtOAcand MeOH. Fractions containing the desired product were combined andconcentrated in vacuo to afford Example 190 (0.128 g). LCMS showedMH⁺=331; T_(RET)=3.64 min.

Example 1914-(Cyclohexylamino)-1-ethyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A mixture of Intermediate 52 (0.014 g, 0.046 mmol), HATU (0.018 g, 0.048mmol) and DIPEA (0.022 ml, 0.125 mmol) in DMF (1 ml) was shaken at roomtemperature for 10 min. 1-[4-(Methylsulfonyl)phenyl]methanamine (0.009g, 0.046 mmol) was then added, and the mixture was shaken for severalminutes to give a solution. This solution was stored at room temperaturefor 16 hours. The solution was concentrated in vacuo, and the residuewas dissolved in chloroform (0.5 ml) and applied to a SPE cartridge(aminopropyl, 0.5 g). The cartridge was eluted successively withchloroform (1.5 ml), EtOAc (1.5 ml) and EtOAc-MeOH (9:1, 1.5 ml).Fractions containing the desired product were concentrated in vacuo toafford Example 191 (0.005 g). LCMS showed MH⁺=470; T_(RET)=2.54 min.

Example 192N-Benzyl-4-(cyclohexylamino)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 192 was prepared from Intermediate 52 using a method analagousto Example 191. LCMS showed MH⁺=392: T_(RET)=2.43.

Example 1934-(Cyclohexylamino)-1-ethyl-N-(4-fluorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 193 was prepared from Intermediate 52 using an analagous methodto Example 191. LCMS showed MH⁺=396; T_(RET)=2.6 min.

Example 1944-(Cyclohexylamino)-1-ethyl-6-methyl-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 194 was prepared from Intermediate 52 using an analagous methodto Example 191. LCMS showed MH⁺=460; T_(RET)=2.74 min.

Example 1954-(Cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 195 was prepared from Intermediate 52 using an analagous methodto Example 191. LCMS showed MH⁺=418; T_(RET)=2.55 min.

Example 196N-Benzyl-1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 196 was prepared from Intermediate 53 using an analagous methodto Example 191. LCMS showed MH⁺=394; T_(RET)=2.02 min.

Example 197N-Benzyl-1-ethyl-4-[(2-oxoazepan-3-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

3-Aminoazepan-2-one (0.043 g, 0.335 mmol, commercially available fromSigma-Aldrich Company Ltd) was added to a mixture of Intermediate 17(0.021 g, 0.067 mmol) and DIPEA (0.058 ml, 0.335 mmol) in acetonitrile(0.5 ml). The resulting mixture was heated at 85° C. for 48 hours.Volatiles were removed in vacuo, and the residue was dissolved inchloroform (0.5 ml) and applied to a SPE cartridge (silica, 0.5 g) whichwas eluted successively with diethyl ether (1.5 ml), ethyl acetate (1.5ml) and ethyl acetate-methanol (9/1, 1.5 ml). Fractions containing thedesired material were concentrated in vacuo to afford Example 197 (0.009g). LCMS showed MH⁺=407; T_(RET)=2.81 min.

Similarly prepared, but replacing the 3-aminoazepan-2-one with the sameor similar number of moles of another amine R³NH₂ were the followingcompounds:

Example Source of Starting Number NHR³ R³NH₂ Material MH⁺ ion T_(RET)(min) Example 198

J. Chem. Soc., Perkin Trans. 1, 1994, 537 Intermediate 17 394 2.75Example 199

Aldrich; or TCI-America Intermediate 17 394 2.82 Example 200

US 4219660 Intermediate 17 380 2.70

Example 201N-Benzyl-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Intermediate 54 (0.048 g, 0.32 mmol) was added to a mixture ofIntermediate 17 (0.050 g, 0.16 mmol) and DIPEA (0.17 ml, 0.98 mmol) inacetonitrile (3 ml). The resulting mixture was heated under reflux.After 12 hours, further quantities of Intermediate 54 (0.044 g, 0.29mmol), DIPEA (0.17 ml, 0.98 mmol) and acetonitrile (1 ml) were added toreaction mixture which was maintained under reflux. After 36 hours, thereaction mixture was concentated in vacuo, and the residual oil wasdissolved in dichloromethane (8 ml) and washed with 5% sodiumbicarbonate solution (2 ml). Evaporation of the organic solution gave aviscous oil which was dissolved in dichloromethane (2 ml) and applied toa SPE cartridge (silica, 5 g). The cartridge was eluted successivelywith a gradient of ethyl acetate-cyclohexane (1:16, then 1:8, 1:4, 1:2,1:1 and 1:0). Fractions containing the desired material wereconcentrated in vacuo to afford Example 201 (0.018 g). LCMS showedMH⁺=392; T_(RET)=2.95 min.

Example 2021-Ethyl-N-(2-hydroxy-1-methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Intermediate 33 (0.1 g, 0.34 mmol), EDC (0.066 g, 0.34 mmol) and HOBT(0.05 g, 0.37 mmol) were suspended in DMF (2 ml) and stirred at roomtemperature under nitrogen for 15 min. 2-aminopropan-1-ol (0.026 g, 0.34mmol) and triethylamine (0.036 g, 0.36 mmol) were added and the mixturewas stirred at room temperature under nitrogen for 6 hours. Solventswere removed in vacuo and the residue partitioned between DCM and water.The organic layer was concentrated and applied to an SPE cartridge(aminopropyl, 5 g), which was eluted with methanol. Concentration invacuo afforded Example 202 (0.095 g). LCMS showed MH⁺=348, T_(RET)=2.15min.

Example 203 Methyl(2S)-2-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)-3-hydroxypropanoate

Reaction scheme:

Intermediate 33 (0.1 g, 0.34 mmol), EDC (0.066 g, 0.34 mmol) and HOBT(0.05 g, 0.37 mmol) were suspended in DMF (2 ml) and stirred at roomtemperature under nitrogen for 15 mins. L-Serine methyl esterhydrochloride (0.054 g, 0.34 mmol) and triethylamine (0.036 g, 0.36mmol) were added and the mixture stirred at room temperature undernitrogen for 18 hours. Solvents were removed in vacuo and the residuewas partitioned between DCM and water. The organic layer wasconcentrated in vacuo and applied to an SPE cartridge (aminopropyl, 5g), which was eluted with methanol. Concentration in vacuo afforded animpure residue which was further purified by SPE cartridge (silica, 5g), eluting with ethyl acetate followed by 5% methanol/ethyl acetate.The desired fractions were concentrated in vacuo to afford Example 203(0.055 g). LCMS showed MH⁺=393; T_(RET)=2.22 min.

Example 204 Ethyl1-ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Intermediate 1 (1.5 g, 5.9 mmol) was dissolved in acetonitrile (80 ml).Trans-4-aminocyclohexanol (0.817 g, 7.1 mmol, commercially availablefrom TCI-America; alternatively (e.g. as the HCl salt) from Aldrich) anddiisopropylethylamine (6.18 ml, 35.5 mmol) were added and the mixturewas stirred at 85° C. for 16 h. The mixture was concentrated in vacuo,and the residue was partitioned between DCM (120 ml) and water (30 ml).The phases were separated and the organic phase was dried (Na₂SO₄) andevaporated to give a pale yellow solid. The solid was dissolved in amixture of DCM (10 ml) and chloroform (3 ml), and applied in equalportions to two SPE cartridges (silica, 20 g) which were elutedsequentially with a gradient of EtOAc:cyclohexane (1:16, then 1:8, 1:4,1:2, 1:1 and 1:0). Fractions containing the desired material werecombined and evaporated in vacuo to give Example 204 (1.893 g) as awhite solid. LCMS showed MH⁺=333; T_(RET)=2.79 min.

Example 205 Ethyl1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Example 204 (1.893 g, 5.7 mmol) was suspended in acetone (12 ml) and thestirred suspension was treated at 0° C. with Jones reagent (1.81 ml).After 30 min, a further quantity of Jones reagent (1.81 ml) was added tothe reaction mixture which was maintained at 0° C. After a further 2 h,a final portion of Jones reagent (1.44 ml) was added to the reactionmixture, and stirring at 0° C. was continued for 1 h. Isopropanol (3.8ml) was added to the reaction mixture, followed by water (15 ml). Theresulting mixture was extracted with ethyl acetate (2×40 ml). Thecombined organic extracts were washed with water (8 ml), dried (Na₂SO₄)and evaporated to a grey solid. The solid was dissolved in DCM (10 ml)and applied in equal portions to two SPE cartridges (silica, 20 g) whichwere eluted sequentially with a gradient of ethyl acetate:cyclohexane(1:16, then 1:8, 1:4, 1:2, and 1:1). Fractions containing the desiredmaterial were combined and evaporated in vacuo to give Example 205(1.893 g) as a white solid. LCMS showed MH⁺=331; T_(RET)=2.84 min.

Example 207 (=Example 5): Ethyl4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Intermediate 1 (2.58 g), Intermediate 6 (2.0 g) andN,N-diisopropylethylamine (8.9 ml) were dissolved in acetonitrile (98ml). The reaction mixture was heated at 85° C. for 24 h then anadditional portion of Intermediate 6 (0.18 g) was added and heatingcontinued for a further 10 h. The reaction was concentrated in vacuo andthe residues partitioned between DCM and water. The phases wereseparated and the organic phase evaporated in vacuo. The residue waspurified by chromatography using Biotage (silica 90 g) eluting with DCM:MeOH (5%) to afford Example 207 (1.55 g) as a white solid. LCMS showedMH⁺ 360; T_(RET)=2.71 min.

Example 209 Ethyl4-[(4-aminocyclohexyl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Example 209 was prepared from Intermediate 1 and(4-aminocyclohexyl)amine using an analogous method to that used for thepreparation of Example 207. LCMS showed MH⁺=332; T_(RET)=2.18 min

Example 2101-Ethyl-N-[(1-oxido-3-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A solution of meta-chloroperoxybenzoic acid (45 mg, 0.26 mmol) inchloroform (1 ml) was added dropwise at 0° C. to a stirred solution ofExample 138 (0.1 g, 0.26 mmol) in chloroform (1.5 ml). After 1.5 h at 0°C., a further quantity of meta-chloroperoxybenzoic acid (45 mg, 0.26mmol) in chloroform (1 ml) was added, and stirring was continued at 0°C. for 1.5 h. A trace of starting material remained, so an additionalquantity of meta-chloroperoxybenzoic acid (22 mg, 0.13 mmol) inchloroform (0.6 ml) was added. After 3.5 h at 0° C., 2M sodium carbonatesolution (1 ml), was added to the reaction mixture.

The phases were separated by passage through a hydrophobic frit and theaqueous phase was extracted with more chloroform (2 ml). The combinedorganic extracts were evaporated to a residual foam which was purifiedby mass directed autoprep HPLC to afford Example 210 (44 mg). LCMSshowed MH⁺=397; T_(RET)=2.13 min.

Example 2111-Ethyl-N-[(1-oxido-2-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 211 was prepared from Example 600 using an analogous method tothat used for the preparation of Example 210. LCMS showed MH⁺=397;T_(RET)=2.20 min

Example 2121-Ethyl-N-[(1-oxido-4-pyridinyl)methyl]4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 212 was prepared from Example 33 using an analogous method tothat used for the preparation of Example 210. LCMS showed MH⁺=397;T_(RET)=2.13 min

Examples 214 to 230

General Procedure

Intermediate 17 (0.15 mmol) was treated with an aliquot of the amine(0.95 ml, equivalent to 0.19 mmol) from a stock solution in acetonitrile(0.2M) and N,N-diisopropylethylamine (0.24 mmol). The mixture was heatedat reflux for 20 h then concentrated in vacuo. The residue was purifiedby SPE (silica) to give the desired product. Source of Starting LC-MCExample no. NHR³ R³NH₂ Material MH⁺ ion Retention time 214

J. Med. Chem., 1994, 37(17), 2360 Intermediate 17 393 2.16 221

Aldrich Intermediate 17 350 3.18 222

Aldrich Intermediate 17 392 3.62 223

Aldrich Intermediate 17 392 3.63, 3.68 224

Pfaltz-Bauer Intermediate 17 392 3.61, 3.66 225

J. Org. Chem., 1985, 50(11), 1859 Intermediate 17 392 3.54 226

Aldrich Intermediate 17 390 3.56 227

Aldrich Intermediate 17 390 3.52 228

WO 99/12933 Intermediate 17 379 2.66 229

EP 1188744 Intermediate 17 393 2.58 230

Aldrich Intermediate 17 405 2.19

Example 225:1-ethyl-4[(1-methylcyclohexyl)amino]-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A preferred method for the preparation of Example 225 involving1-methylcyclohexylamine and a longer reaction time is as follows:

A solution of Intermediate 17 (46 mg), 1-methylcyclohexylamine (26 mg)and diisopropylethylamine (94 mg) in acetonitrile (1 ml) was stirred andheated at reflux for 77 h. More 1-methylcyclohexylamine (102 mg),diisopropylethylamine (93 mg) and acetonitrile (1 ml) were added and thereaction mixture was heated at reflux for a further 68 h. The solutionwas cooled and concentrated in vacuo. The residue was triturated inethyl acetate and filtered. The filtrate was purified by mass directedautoprep. HPLC to give Example 225 (19 mg). LCMS showed MH⁺=392;T_(RET)=3.46 min.

Examples 231, 247 and 257, shown below and also involving1-methylcyclohexylamine, can also preferably be prepared in a similarmanner.

Examples 231-239

General Procedure

Immediate 55 (0.15 mmol) was treated with an aliquot of the amine (0.95ml, equivalent to 0.19 mmol) from a stock solution in acetonitrile(0.2M) and N,N-diisopropylethylamine (0.24 mmol). The mixture was heatedat reflux for 20 h then concentrated in vacuo. The residue was purifiedby SPE (silica) to give the desire product. Source of Starting LC-MCExample no. NHR³ R³NH₂ Material MH⁺ ion Retention time 231

J. Org. Chem., 1985, 50(11), 1859 Intermediate 55 422 3.43 233

Aldrich Intermediate 55 380 3.20 234

Aldrich Intermediate 55 422 3.58 235

Aldrich Intermediate 55 420 3.52 236

Aldrich Intermediate 55 422 3.57, 3.64 237

Pfaltz-Bauer Intermediate 55 422 3.56, 3.62 238

Aldrich Intermediate 55 420 3.48 239

J. Med. Chem., 1994, 37(17), 2360 Intermediate 55 423 2.16

Examples 240-249

General Procedure

Intermediate 56 (0.15 mmol) was treated with an aliquot of the amine(0.95 ml, equivalent to 0.19 mmol) from a stock solution in acetonitrile(0.2M) and N,N-diisopropylethylamine (0.24 mmol). The mixture was heatedat reflux for 20 h then concentrated in vacuo. The residue was purifiedby SPE (silica) to give the desire product. Source of Starting LC-MCExample no. NHR³ R³NH₂ Material MH⁺ ion Retention time 240

Aldrich Intermediate 56 485 3.26 241

Aldrich Intermediate 56 343 2.94 242

Aldrich Intermediate 56 483 3.20 243

Aldrich Intermediate 56 483 3.14 244

Aldrich Intermediate 56 485 3.25, 3.33 245

Pfaltz-Bauer Intermediate 56 485 3.24, 3.31 247

J. Org. Chem., 1985, 50(11), 1859 Intermediate 56 483 3.10 248

J. Med. Chem., 1994, 37(17), 2360 Intermediate 55 423 2.16 249

Aldrich Intermediate 56 471 3.21

Examples 50-258

General Procedure

Intermediate 57 (0.15 mmol) was treated with an aliquot of the amine(0.95 ml, equivalent to 0.19 mmol) from a stock solution in acetonitrile(0.2M) and N,N-diisopropylethylamine (0.24 mmol). The mixture was heatedat reflux for 20 h then concentrated in vacuo. The residue was purifiedby SPE (silica) to give the desire product. Source of Starting MH+ LC-MCExample no. NHR³ NH₂R₃ Material ion Retention time 250

Aldrich Intermediate 57 418 3.78 251

Aldrich Intermediate 57 376 3.42 253

Pfaltz-Bauer Intermediate 57 418 3.78,3.84 254

Aldrich Intermediate 57 418 3.82,3.86 255

Aldrich Intermediate 57 416 3.66 256

Aldrich Intermediate 57 416 3.77 257

J. Org. Chem., 1985, 50(11), 1895 Intermediate 57 418 3.74 258

J. Med. Chem., 1994, 37(17), 2360 Intermediate 57 419 2.38

Examples 259-275

General Procedure

A mixture of Intermediate 58 (0.1 mmol), HATU (0.1 mmol) and DIPEA (0.4mmol) in DMF (0.4 ml) was shaken at room temperature for 10 min. Asolution of the amine (0.1 mmol) in DMF (0.2 ml) was then added and themixture agitated for several minutes to give a solution. The solutionwas stored at room temperature for 16 hours then concentrated in vacuo.The residue was dissolved in chloroform (0.5 ml) and applied to a SPEcartridge (aminopropyl, 0.5 g). The cartridge was eluted successivelywith chloroform (1.5 ml), EtOAc (1.5 ml) and EtOAc:MeOH (9:1, 1.5 ml).Fractions containing the desired product were concentrated in vacuo andthe residue purified by mass directed autoprep HPLC. Source of StartingMH+ LC-MC Example no. NR⁴R⁵ HNR₄R₅ Material ion Retention time 201

Aldrich Intermediate 58 392 2.60 259

EP 666258 Intermediate 58 470 2.44 260

Salor; or ICN Biomedicals, Inc.; or Synthesis, 1982, 12, 1036Intermediate 58 420 3.09 261

CHMSRV-AS; or Matrix Scientific; or Chem. Ber., 1969, 102, 2770Intermediate 58 420 3.09 262

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 58 454 3.20 263

Acros; or Aldrich; Tetrahedron Lett., 2002, 43(48), 8735; or J. Med.Chem., 1984,27(9), 1111; or Org. Lett., 2002, 4(12), 2055 Intermediate58 422 2.86 264

Lis et al., J Med. Chem., 1990 33(10), 2883; see Scheme III and ref. 24Intermediate 58 485 2.64 265

Aldrich Intermediate 58 435 2.54 266

Fluorochem; or WO 98/45268 Intermediate 58 458 2.81 267

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; or Org.Lett., 2002, 4(12), 2055 Intermediate 58 460 2.96 268

Peakdale Intermediate 58 470 2.39 269

Aldrich Intermediate 58 396 2.80 270 (as CF₃CO₂H salt)

Aldrich Intermediate 58 393 1.89 271

TCI-America; or Aldrich; or Maybridge-Int Intermediate 58 418 2.77 272

WO 99/38877 Intermediate 58 427 2.13 273

N.D. Zelinsky Institute Intermediate 58 396 2.15 274

Aldrich Intermediate 58 330 2.10 275

Matrix Scientific Intermediate 58 399 2.29

Example 260 Alternative ProcedureN-[(2,4-dimethylphenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Alternative procedure for preparing Example 260:

A solution of Intermediate 58 (45 mg), HATU (63 mg) and DIPEA (39 mg) inacetonitrile (5 ml) was stirred for 10 min. A solution of2,4-dimethylbenzylamine (24 mg) (available from Salor; or ICNBiomedicals, Inc.; or Synthesis, 1982, 12, 1036) in acetonitrile (1 ml)was added. The reaction mixture was stirred for 18 h. The solution wasconcentrated and the residue partitioned between ethyl acetate (25 ml)and 0.5M sodium bicarbonate (20 ml). The organic phase was separated,washed with water (20 ml), dried over Na₂SO₄ and concentrated to leave agum which was applied to an SPE cartridge (5 g). The cartridge waseluted with ethyl acetate. Fractions containing the desired compoundwere combined and concentrated in vacuo to give Example 260 (32 mg).LC-MS showed MH⁺=420; T_(RET)=3.16 min. δ_(H) (CDCl₃): 1.49 (3H, t),2.11 (2H, m), 2.33 (3H, s), 2.35 (3H, s), 2.40 (2H, m), 2.52 (2H, m),2.61 (2H, m), 4.36 (1H, m), 4.47 (2H, q), 4.55 (2H, d), 6.14 (1H, t),7.01+7.18 (2H, AA′BB′), 7.04 (1H, s), 8.01 (1H, s), 8.36 (1H, s), 9.96(1H, d).

Example 276-287

General Procedure

A mixture of Intermediate 59 (0.1 mmol), HATU (0.1 mmol) and DIPEA (0.4mmol) in DMF (0.4 ml) was shaken at room temperature for 10 min. Asolution of the amine (0.1 mmol) in DMF (0.2 ml) was then added and themixture agitated for several minutes to give a solution. The solutionwas stored at room temperature for 16 hours then concentrated in vacuo.The residue was dissolved in chloroform (0.5 ml) and applied to a SPEcartridge (aminopropyl, 0.5 g). The cartridge was eluted successivelywith chloroform (1.5 ml), EtOAc (1.5 ml) and EtOAc:MeOH (9:1, 1.5 ml).Fractions containing the desired product were concentrated in vacuo andthe residue purified by mass directed autoprep HPLC. Source of StartingMH+ LC-MC Example no. NR⁴R⁵ HNR₄R₅ Material ion Retention time 276

Aldrich Intermediate 59 392 2.60 277

Fluorochem; or WO 98/45268 Intermediate 59 446 2.84 278

Acros; or Aldrich; Tetrahedron Lett., 2002, 43(48), 8735; or J. Med.Chem., 1984,27(9), 1111; or Org. Lett., 2002, 4(12), 2055 Intermediate59 448 3.0 279

Acros Intermediate 59 458 2.40 280

EP 382570 Intermediate 59 458 2.47 281

Aldrich Intermediate 59 384 2.85 282 (as CF₃CO₂H salt)

Aldrich Intermediate 59 381 1.89 283

TCI-America; or Aldrich; or Maybridge-Int Intermediate 59 406 2.80 284

WO 99/28877 Intermediate 59 415 2.14 285

N.D. Zelinsky Institute Intermediate 59 384 2.16 286

Aldrich Intermediate 59 318 2.11 287

Matrix Scientific Intermediate 59 399 2.29

Example 2884-[(4,4-Difluorocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamideand Example 289:1-Ethyl-4-[(4-fluoro-3-cyclohexen-1-yl)amino]-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Diisopropylethylamine (0.113 ml, 0.65 mmol) was added to a stirredmixture of Intermediate 17 (40 mg, 0.13 mmol) and Intermediate 63 (45mg, 0.26 mmol) in acetonitrile (2 ml). The mixture was stirred at 85° C.After 18 h, a further portion of Intermediate 63 (22.5 mg, 0.13 mmol)and diisopropylethylamine (0.113 ml, 0.65 mmol) was added to thereaction mixture and stirring was continued at 90° C. for 24 h. Themixture was then concentrated in vacuo and the residue was partitionedbetween DCM (20 ml) and water (5 ml). The phases were separated and theaqueous phase was extracted with further DCM (10 ml). The combinedorganic extracts were dried (Na₂SO₄) and evaporated in vacuo to give abrown oil (65 mg) which was partially purified on a SPE cartridge(silica, 10 g), eluting with ethyl acetate: petroleum ether (1:8; 1:4;1:2; 1:1 and 1:0). The resulting two-component pale-brown oil (34 mg)was separated by mass directed auto prep HPLC to give Example 288 (19mg) as a white foam (LCMS showed MH⁺=414; T_(RET)=3.24 min) and Example289 (9 mg) as a white solid (LCMS showed MH⁺=394; T_(RET)=3.21 min).

Examples 290-319

General Procedure

A mixture of Intermediate 60 (0.1 mmol), HATU (0.1 mmol) and DIPEA (0.4mmol) in DMF (0.4 ml) was shaken at room temperature for 10 min. Asolution of the amine (0.1 mmol) in DMF (0.2 ml) was then added and themixture agitated for several minutes to give a solution. The solutionwas stored at room temperature for 16 hours then concentrated in vacuo.The residue was dissolved in chloroform (0.5 ml) and applied to a SPEcartridge (aminopropyl, 0.5 g). The cartridge was eluted successivelywith chloroform (1.5 ml), EtOAc (1.5 ml) and EtOAc:MeOH (9:1, 1.5 ml).Fractions containing the desired product were concentrated in vacuo andthe residue purified by mass directed autoprep HPLC. Source of StartingMH+ LC-MC Example no. NR⁴R⁵ HNR₄R₅ Material ion Retention time 290

Aldrich; or TCI-America; or Maybridge-Int Intermediate 60 447 2.96 291

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 60 488/ 490 3.16 292

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; or Org.Lett., 2002, 4(12), 2055 Intermediate 60 439 2.84 293

Aldrich Intermediate 60 457 2.92 294

Aldrich Intermediate 60 457 2.87 295

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 60 489 3.06 296

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; or Org.Lett., 2002, 4(12), 2055 Intermediate 60 489 3.08 297

Aldrich Intermediate 60 457 2.82 298

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; or Org.Lett., 2002, 4(12), 2055 Intermediate 60 455 2.98 299

Aldrich; or Acros; or Jung et al., Tetrahedron Lett., 2002, 43(48),8735, or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; or Org. Lett.,2002, 4(12), 2055 Intermediate 60 451 2.79 300

Aldrich Intermediate 60 437 2.82 301

Peakdale Molecular Ltd Intermediate 60 528 2.76 302

Aldrich Intermediate 60 461 3.00 303

Peakdale Molecular Ltd Intermediate 60 464 2.31 304

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 60 489 3.16 305

Aldrich; or Org. Lett., 2002, 4(12), 2055 Intermediate 60 439 2.84 306

Fluka Intermediate 60 473 2.92 307

Fluorochem Ltd; or WO 98/45268 Intermediate 60 487 2.95 308

Apin Intermediate 60 485 2.94 309

Key Organics Ltd Intermediate 60 456 2.65 310

J. Med. Chem., 2001, 44(26), 4628 Intermediate 60 481 3.16 311

Manchester Organics Ltd Intermediate 60 428 2.28 312

Acros Chimica Intermediate 60 499 2.37 313

Aldrich Intermediate 60 511 3.18 314

Lis et al., J Med. Chem., 1990 33(10), 2883; see Scheme III and ref. 24Intermediate 60 514 2.60 315

WO 94/17035 Intermediate 60 478 2.47 316

Sigma Intermediate 60 500 2.50 317

Peakdale Molecular Ltd Intermediate 60 478 2.49 318

WO 02/85860 Intermediate 60 464 2.42 319

Syngene Intermediate 60 452 2.45

Example 3201-Ethyl-N-4-piperidinyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A solution of hydrogen chloride in dioxan (30 ml, 4M, 0.12 mol) wasadded to a suspension of Example 126 (1.3 g, 2.75 mmol), in dioxan (10ml) and the mixture was stirred at room temperature for 6 h. Thereaction mixture was left to stand for 14 h, then the solution wasevaporated, azeotroping with DCM to give a white solid the hydrochloridesalt. The solid was suspended in ethyl acetate (50 ml) and washed withsodium hydroxide solution (2N, 50 ml). The organic layer was dried overNa₂SO₄ and concentrated in vacuo to give Example 318 as a white solid(995 mg). LCMS showed MH⁺=373; T_(RET)=1.89 min.

Example 321 1-Ethyl-N-(4-piperidinylmethyl)-4-(tetrahydro-2H-pyran-4ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A solution of hydrogen chloride in dioxan (30 ml, 4M, 0.12 mol) wasadded to a suspension of Intermediate 72 (1.2 g, 2.5 mmol), in dioxan(10 ml) and the mixture was stirred at room temperature for 6 h. Thereaction mixture was left to stand for 14 h, then the solution wasevaporated, azeotroping with DCM to give a white solid (1.24 g). Aportion of the solid (68 mg) was suspended in ethyl acetate and washedwith 2M-sodium hydroxide solution. The organic layer was dried overNa₂SO₄ and concentrated in vacuo to afford Example 321 as a white solid(60 mg). LCMS showed MH⁺=387; T_(RET)=1.92 min.

Example 3221-Ethyl-N-[1-(ethylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Triethylamine (0.023 ml, 0.16 mmol) was added to a solution of Example320 (0.043 g, 0.115 mol) in DCM (1 ml). The mixture was cooled(ice/water bath for 10 min) and ethane sulfonyl chloride (0.014 ml,0.138 mmol) was added. The resultant solution was stirred at roomtemperature for 18 h, then the solvent was removed with a steam ofnitrogen. The residue was dissolved in dichloromethane (1.5 ml) andstirred with water (1.5 ml). The organic layer was separated and blowndown with nitrogen, and applied to a SPE cartridge (silica, 2 g) elutingwith 60%-100% ethyl acetate in cyclohexane. The desired fractions wereconcentrated in vacuo to afford Example 322 as a white solid (32 mg).LCMS showed MH⁺=465; T_(RET)=2.52 min Similarly prepared were thefollowing, using the same or a similar number of moles of reagents andthe same or similar volumes of solvents:

Sulfonyl Source of MH+ LC-MC Example no. NR⁴R⁵ chloride sulfonylchloride ion Retention time 323

Aldrich 479 2.58 324

J. Org. Chem., 1952, 17, 1529 505 2.75 325

Aldrich 451 2.41 326

Aldrich 527 2.90 327

Aldrich 513 2.66 328

Aldrich 479 2.42

Example 329N-[1-(Cyclopropylcarbonyl)-4-piperidinyl]-ethyl(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Cyclopropane carboxylic acid (0.011 ml, 0.138 mmol), EDC (0.031 g, 0.161mmol) and HOBT (0.019 g, 0.138 mmol) were suspended in DMF (2 ml) andstirred at room temperature for 1 h. Example 320 (0.043 g, 0.115 mmol)was added and the mixture was stirred at room temperature for 16 hours.Most of the solvent was removed using a stream of nitrogen and theresidue was partitioned between DCM (3 ml) and water (3 ml). The organiclayer was blown down with nitrogen and applied to a SPE cartridge(aminopropyl, 1 g), which was eluted with methanol. Concentration byblowing down with nitrogen afforded an impure residue which was furtherpurified by SPE cartridge (silica, 1 g), eluting with 50-100% EtOAc incyclohexane followed by 5% methanol in EtOAc. The desired fractions wereconcentrated in vacuo to afford Example 329 as a white solid (49 mg).LCMS showed MH⁺=441; T_(RET)=2.23 min Similarly prepared, using the sameor similar numbers of moles of reagents and volumes of solvents, andusing Example 320 as the starting material to make Examples 330 to 343,but using Example 321 (similar number of moles) instead of Example 320as the starting material to make Examples 344 to 349, were thefollowing:

Carboxylic Source of MH+ LC-MC Example no. NR⁴R⁵ acid Carboxylic acidion Retention time 330

Aldrich 467 2.50 331

Aldrich 471 2.73 332

Aldrich 471 2.72 333

Aldrich 483 2.81 334

Aldrich 443 2.27 335

Combi-Blocks 485 2.17 336

Aldrich 429 2.38 337

Aldrich 472 2.20 338

Synchem OHG 500 1.91 339

J. Med. Chem., 1998, 41(5), 760 497 2.17 340

Micro- Chemistry Building Blocks 498 1.94 341

Interchim Intermediates 498 2.07 342

DE 3618135 471 2.33 343

Aldrich 509 2.75 344

Aldrich 485 2.78 345

Aldrich 497 2.85 346

Aldrich 455 2.50 347

J. Med. Chem., 1998, 41(5), 760 511 2.42 348

Aldrich 523 2.78 349

Interchim Intermediates 512 2.29

Example 350 Methyl3-[(1-ethyl-5-{[phenylmethyl)amino]carbonyl}-1H-pyrazolo[3,4-b]pyridin-4-yl)amino]cyclohexanecarboxylate

Example 350 was prepared from Intermediate 17 and using an analogousmethod to that used for the preparation of Example 207. LCMS showedMH⁺=436; T_(RET)=3.20. Example 3513-[(1-Ethyl-5-{[(phenylmethyl)amino]carbonyl}-1H-pyrazolo[3,4-b]pyridin-4-yl)amino]cyclohexanecarboxylicacid

2M-Sodium hydroxide solution (0.5 ml) was added to a stirred suspensionof Example 350 (0.12 g, 0.275 mmol) in methanol (3.5 ml) and water (0.8ml). After stirring overnight at room temperature, the reaction solutionwas concentrated, diluted with water (3 ml) and acidified with2M-hydrochloric acid. The resulting precipitate was collected byfiltration, washed with water and dried to give Example 351, as a whitesolid (0.105 g). LCMS showed MH⁺=422; T_(RET)=2.95 min.

Example 3521-Ethyl-N-(phenylmethyl)-4-(4-piperidinylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Aqueous hydrochloric acid (20 ml, 5M) was added to a solution ofIntermediate 65 (2.58 g, 5.40 mmol) in tetrahydrofuran (10 ml). Thereaction mixture was stirred at 20° C. for 22 h then evaporated invacuo. The residue was partitoned between DCM and water. The aqueousphase was basified with aqueous sodium hydroxide solution (2M) andextracted with diethyl ether. The organic phases was evaporated in vacuoto give Example 352 as a white solid (2.04 g). LCMS showed MH⁺=379;T_(RET)=2.10 min.

Example 353 Ethyl1-ethyl-4-({1-[(methyloxy)acetyl]-4-piperidinyl}amino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Methoxyacetyl chloride (0.016 mg, 0.144 mmol) and triethylamine (0.02mol, 0.144 mmol) were added to a solution of Example 352 (0.046 g, 0.122mmol) in DCM in a Reactivial. The reaction was stirred for 22 h at 20°C. then diluted with DCM and washed with aqueous sodium hydrogencarbonate solution. The organic phase was separated and applied directlyto a SPE cartridge (silica 2 g). The cartridge was eluted with DCM:MeOH(1% followed by 3%) to give Example 353 as a white solid (0.05 g). LCMSshowed MH⁺=451; T_(RET)=2.66 min.

Example 354 Ethyl1-(1-methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Prepared in a similar manner to example 186 using Example 20 (0.03 g,0.1 mmol), with isopropylbromide (10 uL, 0.11 mmol), a further 0.11 mmolof alkylating agent was added after 16 hours. The final compound wasformed as a clear gum (16 mg). LCMS showed MH⁺=333; T_(RET)=3.16 min.

Example 3554-(Cyclohexylamino)-1-ethyl-N-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Intermediate 64 (0.02 g, 0.084 mmol) and diisopropylethylamine (0.044ml, 0.252 mmol) were suspended in N-methylpyrrolidinone (1 ml) andcyclohexylamine (0.012 ml, 0.1 mmol) was added. The mixture was heatedat 85° C. with stirring in a Reactivial™ for 8 h, then concentrated invacuo. The residue was partitioned between DCM (2 ml) and water (2 ml).The layers were separated and the organic layer was concentrated invacuo, then purified by mass directed autoprep HPLC to afford Example355 (0.012 g). LCMS showed MH⁺=302; T_(RET)=2.85 min.

Example 3561-Ethyl-N-(4-fluorophenyl)-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 356 was prepared from Intermediate 53 using an analogous methodto Example 191. LCMS showed MH⁺=398; T_(RET)=2.18 min.

Example 3571-Ethyl-6-methyl-N-{[4-(methylsulfonyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 357 was prepared from Intermediate 53 using an analogous methodto Example 191. LCMS showed MH⁺=472; T_(RET)=2.15 min.

Example 358N-(2,3-Dihydro-1H-inden-2-yl)-1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 358 was prepared from Intermediate 53 using an analogous methodto Example 191. LCMS showed MH⁺=394; T_(RET)=2.04 min.

Examples 360-414

General Procedure

Intermediate 33 (1.89 g) was treated with thionyl chloride (10 ml) andthe mixture heated under reflux for 2 h. Excess thionyl chloride wasremoved in vacuo to afford Intermediate 73, presumed to be the acidchloride of Intermediate 33 as a cream solid. The solid was suspended intetrahydrofaran (32.5 ml) and an aliquot of the suspension added to amixture of the amine (0.1 mmol) and N,N-diisopropylethylamine(0.165-0.22 mmol) in TBF (0.5 ml). The reaction mixture was agitated for24 h and the solvent removed in vacuo. The residue was purified by massdirected autoprep HPLC. Example Source of Starting MH+ LC-MC NumberNR⁴R⁵ HNR⁴R⁵ Material ion Retention time 360

Interchim Intermediates Intermediate 33 477 2.98 361

Aldrich Intermediate 33 408 3.45 362

Aldrich Intermediate 33 384 3.09 363

Butt Park Ltd. Intermediate 33 437 2.69 364

Aldrich Intermediate 33 432 3.21 365

Maybridge Chemical Company Ltd. Intermediate 33 437 2.72 366

Aldrich Intermediate 33 382 2.67 367

Interchim Intermediates Intermediate 33 519 3.01 368

Aldrich Intermediate 33 367 2.19 369

Butt Park Ltd. Intermediate 33 492 2.21 370

J. Chem. Soc. C, 1969, 1444 Intermediate 33 449 2.72 371

Peakdale Technologies Limited M Intermediate 33 444 2.81 372

J. Heterocycl. Chem., 1975, 12(2), 225 Intermediate 33 437 2.74 373

Interchim Intermediates Intermediate 33 459 2.79 374

Apollo Scientific Ltd. Intermediate 33 400 2.99 375

Aldrich Intermediate 33 400 3.35 376

Lancaster Intermediate 33 425 3.07 377

Maybridge CombiChem Intermediate 33 513 3.33 379

Peakdale Technologies Limited Intermediate 33 444 2.99 380

J. Heterocycl. Chem., 1975, 12(2), 225 Intermediate 33 437 2.64 381

Interchim Intermediates Intermediate 33 479 2.68 382

Aceto Corporation Intermediate 33 425 3.38 383

Aldrich Intermediate 33 382 2.78 384

Aldrich Intermediate 33 400 3.38 386

WO 03/32986 Intermediate 33 467 2.65 387

Maybridge Chemical Company Ltd. Intermediate 33 513 3.35 388

Intermediate 67 Intermediate 33 505 3.23 389

Lancaster Intermediate 33 451 3.17 390

EP 538945 Intermediate 33 487 2.80 391

Aldrich Intermediate 33 416 2.99 392

Interchim Intermediates Intermediate 33 459 2.74 393

Butt Park Ltd. Intermediate 33 423 2.66 394

Aldrich Intermediate 33 434 3.43 395

Aldrich Intermediate 33 367 2.40 396

Aldrich; or Reetz, Synthesis, 1999, 9, 1555 Intermediate 33 434 3.67 397

Bayer AG Intermediate 33 479 2.89 398

Exploratory Library Intermediate 33 451 2.91 399

Maybridge Chemical Company Ltd. Intermediate 33 515 3.02 400

TimTec Intermediate 33 492 2.20 401

Exploratory Library Intermediate 33 437 2.68 402

Lancaster Intermediate 33 468 3.53 403

Heterocycles, 1983 20(3), 445 Intermediate 33 437 2.70 404

Aldrich Intermediate 33 400 3.09 405

Aldrich Intermediate 33 418 3.21 406

Aldrich Intermediate 33 384 3.19 407

Aldrich Intermediate 33 409 2.95 408

Helv. Chim. Acta, 1983 66(4), 1046 Intermediate 33 472 3.07 409

Butt Park Ltd. Intermediate 33 437 2.68 411

Salor Intermediate 33 444 2.69 413

Peakdale Molecular Limited Intermediate 33 437 2.35

Example 4141-Ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Example 414 was prepared from Intermediate 59 using the general methoddescribed for Examples 360-413 method. LCMS showed MH⁺=398; T_(RET)=2.90min.

Examples 415-487

General Procedure

A mixture of Intermediate 61 (0.1 mmol), HATU (0.1 mmol) and DIPEA (0.4mmol) in DMF (0.4 ml) was shaken at room temperature for 10 min. Asolution of the amine (0.1 mmol) in DMF (0.2 ml) was then added and themixture agitated for several minutes to give a solution. The solutionwas stored at room temperature for 16 hours then concentrated in vacuo.The residue was dissolved in chloroform (0.5 ml) and applied to a SPEcartridge (aminopropyl, 0.5 g). The cartridge was eluted successivelywith chloroform (1.5 ml), EtOAc (1.5 ml) and EtOAc:MeOH (9:1, 1.5 ml).Fractions containing the desired product were concentrated in vacuo andthe residue purified by mass directed autoprep HPLC. Example Source ofStarting MH+ LC-MC number NR⁴R⁵ HNR⁴R⁵ Material ion Retention time 415

Rare Chemicals GmbH Intermediate 61 395 2.80 416

Aldrich Intermediate 61 345 2.64 417

Ultrafine (UFC Ltd) Intermediate 61 409 2.84 418

Intermediate 8A; or Intermediate 8 (CombiBlocks) Intermediate 61 3723.03 419

N.D. Zelinsky Institute Organic Chemistry Intermediate 61 382 2.96 420

Peakdale Molecular Ltd. Intermediate 61 456 3.22 421

Peakdale Molecular Ltd. Intermediate 61 421 3.03 422

Aldrich Intermediate 61 372 3.09 423

J. Org. Chem., 1955, 20, 1657 Intermediate 61 485 3.44 424

Key Organics Ltd Intermediate 61 413 3.39 425

Acros Intermediate 61 456 3.19 426

WO 00/17163 Intermediate 61 409 3.3 427

Peakdale Molecular Ltd. Intermediate 61 421 3.23 428

Peakdale Molecular Ltd. Intermediate 61 435 3.07 429

Peakdale Molecular Ltd. Intermediate 61 421 2.97 430

Apin Intermediate 61 394 3.25 431

Acros; or Aldrich; or Jung et al., Tetrahedron Lett., 2002, 43(48),8735; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; or Org. Lett.,2002, 4, 2055 Intermediate 61 408 3.51 432

Aldrich Intermediate 61 414 3.68 433

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 61 446 3.81 434

J. Med. Chem., 1999, 42(14), 2504 Intermediate 61 471 3.23 435

Aldrich Intermediate 61 414 3.66 436

Aldrich; or Organic Letters, 2002, 4(12), 2055 Intermediate 61 392 3.69438

Key Organics Ltd Intermediate 61 485 3.25 439

Buttpark Intermediate 61 394 3.52 440

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 61 446 4 441

Lancaster; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 61 446 4.08 442

Aldrich Intermediate 61 392 3.62 443

Aldrich Intermediate 61 418 3.83 444

WO 01/38323 Intermediate 61 440 3.07 445

Aldrich Intermediate 61 408 3.31 446

Acros Intermediate 61 471 3.13 447

Peakdale Molecular Ltd. Intermediate 61 435 3.13 448

Peakdale Molecular Ltd. Intermediate 61 456 3.32 449

Peakdale Molecular Ltd. Intermediate 61 436 3.56 450

Aldrich Intermediate 61 471 2.79 451

J. Med Chem., 1982, 25(12), 1442 Intermediate 61 465 3.11 452

ABCR Intermediate 61 464 3.47 453

Matrix Scientific; or Chem. Ber., 1969, 102, 2770 Intermediate 61 4073.35 454

Aldrich Intermediate 61 411 3.18 455

Aldrich Intermediate 61 407 3.3 456

Aldrich Intermediate 61 423 3.09 457 (as CF₃C(O)OH salt)

Aldrich Intermediate 61 379 2.92 458

Aldrich Intermediate 61 414 3.68 459

Aldrich Intermediate 61 404 3.72 460 (as CF₃C(O)OH salt)

Aldrich Intermediate 61 421 3.29 461

Aldrich Intermediate 61 396 3.58 462

Aldrich Intermediate 61 438 3.53 463 (as CF₃C(O)OH salt)

Inorganic Chemicals 1997, 36(9), 1967 Intermediate 61 413 3.4 464 (asCF₃C(O)OH salt)

Peakdale Molecular Ltd. Intermediate 61 449 3.18 465

ABCR Intermediate 61 422 3.77 466

Aldrich Intermediate 61 404 3.72 467

Pfaltz-Bauer; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 61 446 3.85 468

Peakdale Molecular Ltd. Intermediate 61 436 3.53 469

Aldrich Intermediate 61 404 3.66 470

Aldrich Intermediate 61 435 3.52 471

Esprit Intermediate 61 370 2.82 472

Apollo Intermediate 61 444 3.63 473

MicroChemistry RadaPharma Intermediate 61 399 3.16 474

Fluka Intermediate 61 430 3.72 475

J. Am. Chem. Soc., 1977, 99, 3075 Intermediate 61 421 3.04 477

J. Org. Chem., 2001, 66(6), 1999 Intermediate 61 421 2.89 478

Aldrich Intermediate 61 396 3.59 479

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 61 446 3.80 480

Aldrich Intermediate 61 414 3.57 481

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 61 396 3.62 482

Aldrich Intermediate 61 446 3.82 483

J. Med. Chem., 2001, 44(26), 4628 Intermediate 61 438 3.95 484

WO 9417035 Intermediate 61 485

Aldrich Intermediate 61 394 3.61 486

MicroChemistry- RadaPharma Intermediate 61 395 2.78 487

Aldrich Intermediate 61 379 2.71

Example 4884-[({[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoicacid

2M-Sodium hydroxide solution (29 μL, 0.058 mmol) was added to a stirredsolution of Example 470 (6 mg, 0.014 mmol) in methanol (28 μL) and water(2 μL). The resulting solution was stirred at 50° C. under nitrogen.After 16 h, the mixture was diluted with water (0.5 ml) and adjusted topH 4 with acetic acid. The precipitated solid was collected byfiltration and dried in vacuo to afford Example 488 as a white solid(4.5 mg). LCMS showed MH⁺=422; T_(RET)=3.26 min.

Example 4893-[({[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoicacid

2M-Sodium hydroxide solution (83 μL, 0.166 mmol) was added to a stirredsolution of Example 468 (18 mg, 0.042 mmol) in methanol (88 μL) andwater (5 μL). The resulting solution was stirred at 50° C. undernitrogen. After 16 h, a further quantity of 2M-sodium hydroxide solution(29 μL, 0.058 mmol) was added to the reaction mixture. After 24 h, thereaction mixture was diluted with water (0.5 ml) and adjusted to pH 4with acetic acid. The mixture was extracted with ethyl acetate (2×0.5ml), and the combined extracts were dried (Na₂SO₄) and evaporated invacuo to give a solid (21 mg). This solid was purified on an SPEcartridge (silica, 1 g) eluting with ethyl acetate:cyclohexane (1:1)followed by methanol. Fractions containing the desired product werecombined and concentrated to afford Example 489 as a white solid (4.6mg). LCMS showed MH⁺=422; T_(RET)=3.22 min.

Example 4904-(Cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamidehydrochloride

A solution of Example 469 (71 mg, 0.17 mmol) in anhydrous THF (2 ml) wastreated with hydrogen chloride in dioxane (4M, 0.3 ml). After standingat ambient temperature for 16 hours the resulting solid was collected byfiltration and dried under vacuum to give Example 490 as rod likecrystals (36 mg). LCMS showed MH⁺=404; T_(RET)=3.60 min.

Example 4914-(Cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamidemethanesulphonate

A solution of Example 469 (71 mg, 0.17 mmol) in anhydrous THF (2 ml) wastreated with anhydrous methane sulphonic acid (11.4 μL, 0.17 mmol).After standing at ambient temperature for 16 hours the resulting solidwas collected by filtration and dried under vacuum to give Example 491as rod like crystals (23 mg). LCMS showed MH⁺=404; T_(RET)=3.59 min.

Examples 492-649

General Procedure

A mixture of Intermediate 33 (0.1 mmol), HATU (0.1 mmol) and DIPEA (0.4mmol) in DMF (0.4 ml) was shaken at room temperature for 10 min. Asolution of the amine (0.1 mmol) in DMF (0.2 ml) was then added and themixture agitated for several minutes to give a solution. The solutionwas stored at room temperature for 16 hours then concentrated in vacuo.The residue was dissolved in chloroform (0.5 ml) and applied to a SPEcartridge (aminopropyl, 0.5 g). The cartridge was eluted successivelywith chloroform (1.5 ml), EtOAc (1.5 ml) and EtOAc:MeOH (9:1, 1.5 ml).Fractions containing the desired product were concentrated in vacuo andthe residue purified by mass directed autoprep HPLC. LC-MC ExampleSource of Starting MH + Retention number NR⁴R⁵ HNR⁴R⁵ Material ion time492 (as CF₃C(O)OH salt)

Peakdale Molecular Ltd. Intermediate 33 453 2.90 493

Maybridge Chemical Company Ltd.; or WO 01/30745 Intermediate 33 428 2.92494

Trans World Chemicals, Inc.; or DE 1953059 Intermediate 33 428 2.91 495

Fluorochem Ltd. Intermediate 33 446 2.70 496

Peakdale Molecular Ltd. Intermediate 33 438 2.83 497

Peakdale Molecular Ltd. Intermediate 33 438 2.79 498

Fluorochem Ltd. Intermediate 33 446 2.73 499

Aldrich Intermediate 33 426 2.50 500

Nippon Kagaku Zasshi; 1952, 73; 393 Intermediate 33 438 2.62 501

Apollo Scientific Intermediate 33 462 2.88 502

Apin Chemicals Ltd. Intermediate 33 437 2.19 503

Sigma Intermediate 33 410 2.60 504

Aldrich Intermediate 33 428 2.80 505

Miteni S.p.A. Intermediate 33 478 2.97 506

Aldrich Intermediate 33 424 2.58 507

J. Med. Chem, 1997, 20(9), 1210 Intermediate 33 436 2.44 508

Fluorochem Ltd. Intermediate 33 462 2.99 509

JP 11080156 Intermediate 33 473 2.2 510

Aldrich Intermediate 33 454 2.41 512

Synchem OHG Intermediate 33 462 2.96 513

Apin Chemicals Ltd. Intermediate 33 454 2.59 514

J. Chem. Soc. Perkin Trans. 1, 1977, 386 Intermediate 33 438 2.75 515

SIGMA-RBI Intermediate 33 430 2.65 516

WO 9303022 Intermediate 33 454 2.67 517

SIGMA-RBI Intermediate 33 408 2.73 518

Matrix Scientific; or Chem. Ber., 1969, 102, 2770 Intermediate 33 4083.2 519

J. Med. Chem, 1982 25(12), 1442 Intermediate 33 466 3 521

Acros Intermediate 33 473 2.62 522

WO 01/38323 Intermediate 33 445 2.55 523

Aldrich Intermediate 33 394 3 524

Aldrich Intermediate 33 423 2.51 525

Aldrich Intermediate 33 412 3.06 526

Aldrich Intermediate 33 408 3.16 527

Yakugaku Zasshi; 1950 70, 71 Intermediate 33 459 2.6 528

Aldrich; or Organic Letters, 2002, 4(12), 2055 Intermediate 33 394 3.08530

Lancaster Intermediate 33 466 3.31 531

J. Am. Chem. Soc., 1976, 78(22), 6978 Intermediate 33 438 3 532 (asCF₃C(O)OH salt)

Inorganic Chemistry, 1997, 36(9), 1967 Intermediate 33 415 2.82 533

Aldrich Intermediate 33 406 3.14 534

Peakdale Molecular Ltd. Intermediate 33 451 2.71 535

Aldrich Intermediate 33 406 3.15 536

Aldrich Intermediate 33 406 3.15 537

J.Med. Chem., 1999, 42(14), 2504 Intermediate 33 473 2.58 538

Chemical Building Blocks Intermediate 33 422 2.92 540

Aldrich Intermediate 33 451 2.13 541

Aldrich Intermediate 33 436 3.15 542

Aldrich Intermediate 33 408 2.85 544

Janssen Pharma- ceuticals Intermediate 33 449 2.67 545

Intermediate 69 Intermediate 33 444 2.34 546 (as H—C(O)OH salt = formicacid addition salt)

Arzneimittel Forsching, 1974, 24(4a), 584 Intermediate 33 430 1.95 547

WO 97/25323 Intermediate 33 445 1.96 548 (as CF₃C(O)OH salt)

WO 03/32980 Intermediate 33 479 2.21 549 (as CF₃C(O)OH salt)

WO 03/32980 Intermediate 33 492 2.24 550 (as CF₃C(O)OH salt)

WO 02/85860 Intermediate 33 424 2.33 551

Salor Intermediate 33 422 3.36 552

WO 95/00516 Intermediate 33 494 3.22 553 (as CF₃C(O)OH salt)

WO 03/32980 Intermediate 33 492 2.21 554

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 33 448 3.4 555

Aldrich Intermediate 33 416 3.06 556

Salor Intermediate 33 432 3.21 557

DE 2300018 Intermediate 33 458 3.12 558

Peakdale Molecular Ltd Intermediate 33 436 3.41 559 (as CF₃C(O)OH salt)

JP 10045736 Intermediate 33 463 2.28 560

WO 02/16318 EP 338793 Intermediate 33 487 2.74 561

Maybridge Chemical Company Ltd. Intermediate 33 440 2.99 562

Lancaster Intermediate 33 440 3.00 563

Aldrich Intermediate 33 398 3.01 564

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 33 416 3.11 565

Aldrich; or Organic Letters, 2002, 4(12), 2055 Intermediate 33 414 3.19567

Aldrich Intermediate 33 372 3.01 568

J. Biol. Chem., 1997, 272(3), 1493 Intermediate 33 472 2.69 569

Fluorochem Lt. Intermediate 33 466 3.29 570

Intermediate 71 Intermediate 33 463 2.66 571

Maybridge Reactive intermediates Intermediate 33 478 2.25 572

WO 99/67204 Intermediate 33 463 2.24 573

Eur. J. Med. Chem., 1987, 22(5), 417 Intermediate 33 450 2.90 574

Lancaster Intermediate 33 446/ 448/ 450 3.35 575

Eur. J. Med. Chem., 1987, 33(5), 363 Intermediate 33 436 3.48 576

Avocado Intermediate 33 416 3.06 577

WO 02/30930 Intermediate 33 458 2.80 578

Apin Intermediate 33 458 2.80 579

Aldrich Intermediate 33 458 2.80 580

Aldrich Intermediate 33 581

Lancaster; or J. Med. Chem., 1984, 27(9), 1111. Intermediate 33 446/448/ 450 2.80 582

Aldrich Intermediate 33 440 2.96 583

Aldrich Intermediate 33 410 2.98 584

ICN Biomedicals, Inc.; or Salor; or Synthesis, 1982, 12, 1036Intermediate 33 408 3.18 585

WO 03/32986 Intermediate 33 437 2.62 586

Aldrich Intermediate 33 424 3.05 587

Aldrich Intermediate 33 414/ 416 3.13 588

Buttpark Intermediate 33 396 2.14 589

Aldrich Intermediate 33 424 2.76 590

Lancaster Intermediate 33 396 2.95 591

Aldrich; or Synlett, 1999, 4, 409 Intermediate 33 386 3.10 592

Aldrich Intermediate 33 593

Apin Intermediate 33 438 2.82 594

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111.Intermediate 33 448/ 450/ 452 3.26 595

WO 02/85860 Intermediate 33 423 2.29 596

Aldrich Intermediate 33 416 3.0 597

Aldrich Intermediate 33 423 2.56 598

Apin Intermediate 33 396 2.54 599

WO 00/17163 Intermediate 33 411 2.72 600

Aldrich; or J. Med. Chem., 2003, 46(4), 461. Intermediate 33 381 1.89601

Aldrich; or Meindl et al., J.Med. Chem., 1984, 27(9), 1111. Intermediate33 448 2.96 602

Peakdale Molecular Limited Intermediate 33 423 2.28 603

WO 94/17035 Intermediate 33 437 2.28 604

J.Pharm, Sci., 1987, 76(1), 18-20 Intermediate 33 437 2.34 605

Aldrich; or Meindl et al., J.Med.Chem., 1984, 27(9), 1111; or OrganicLetters, 2002, 4(12), 2055 Intermediate 33 398 2.71 606

Lis et al., J. Med. Chem., 1990, 33(10), 2883, see Scheme III and ref.24 Intermediate 33 473 2.40 607

Sigma Intermediate 33 459 2.31 608

Peakdale Molecular Ltd. Intermediate 33 423 2.55 609

Fluorochem Ltd. Intermediate 33 446 2.82 610

DE 19937494 Intermediate 33 437 1.86 611

FluorochemL Intermediate 33 444 2.80 612

WO00/72834 Intermediate 33 415 2.12 613

Aldrich Intermediate 33 448 2.96 615

J. Med. Chem., 2001, 44(26), 4628 Intermediate 33 440 3.03 616

Intermediate 75 (as HCl salt) Intermediate 33 451 2.62 617

Aldrich; or Organic Letters, 2002, 4(12), 2055 Intermediate 33 398 2.90618

Alfa Intermediate 33 466 2.98 619

Energy & Fuels, (1994), 8(4), 990-1001 Intermediate 33 408 2.86 620

Alfa Intermediate 33 466 2.94 621

Apollo Intermediate 33 434 2.82 622

Acros Intermediate 33 432 2.9 623

Acros Intermediate 33 476 2.95 624

Apollo; or Eur.J.Med. Chem.,1998, 33(5),363 Intermediate 33 408 2.88 625

Maybridge Intermediate 33 408 2.83 626

Lancaster Intermediate 33 448 3.02 627

Apin Intermediate 33 405 2.56 628

Ubi-Chem Intermediate 33 458 2.89 629

ABCR Intermediate 33 466 2.97 630

Lancaster Intermediate 33 505.9 2.97 631

Apollo Intermediate 33 436 3.11 632

WO 98/33767; or Meindl et al., J.Med. Chem., 1984, 27(9), 1111.Intermediate 33 405 2.55 633

Pfaltz-Bauer; or Meindl et al., J. Med. Chem., 1984, 27(9),1111Intermediate 33 448 2.88 634

Transworld Intermediate 33 428 3.22 635

Apin (HNR⁴R⁵used as HCl salt) Intermediate 33 536 3.47 636

Matrix Intermediate 33 408 3.18 637

Avocado Intermediate 33 466 3.25 638

Pfaltz-Bauer Intermediate 33 505.9 2.92 639

Alfa Intermediate 33 458 3.10 640

WO 03/35621 (HNR⁴R⁵used as HCl salt) Intermediate 33 410 2.49 641

WO 03/35621 (HNR⁴R⁵used as HCl salt) Intermediate 33 410 2.51 642

DE 2136624 (HNR⁴R⁵used as HCl salt) Intermediate 33 424 2.55 643

(HNR⁴R⁵used as HCl salt) Intermediate 33 478 2.96 644

Aldrich Intermediate 33 462 3.13 645

Intermediate 33 436 3.18 646

Matrix Intermediate 33 408 2.84 647

Apollo Intermediate 33 434 2.80 648

ABCR Intermediate 33 466 2.99 649

Lancaster Intermediate 33 428 2.87

Example 518N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;also known as:N-(3,4-dimethylbenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

An alternative process for preparing Example 518 is given below:

To a solution of Intermediate 33 (3.5 g, 12.07 mmol) in DMF (500 ml) wasadded HATU (4.5 g, 12.07 mmol) and the mixture stirred at roomtemperature for 30 min. 3,4-Dimethylbenzylamine (1.63 g, 12.07 mmol,obtainable from Matrix Scientific, Columbia, USA or by a processdescribed in Chem. Ber., 1969, 102, 2770) was added followed by DIPEA(4.5 ml, 26.55 mmol) and the solution stirred at room temperature for 16hours. The solvent was removed under reduced pressure and the residuepartitioned between saturated aqueous NaHCO₃ (200 ml) and ethyl acetate(250 ml), the aqueous phase re-extracted with ethyl acetate (2×200 ml),the organic extracts combined, dried (Na₂SO₄) and evaporated. Theresultant viscous oil was recrystallised from hot ethyl acetate (ca. 100ml) to give the title compound as a white crystalline solid (3.36 g,80%). LCMS showed MH⁺=408; T_(ret)=3.06 min. 8H P6 DMSO) 1.36 (3H, t),1.51 (2H, m), 2.00 (2H, m), 2.18 (3H, s), 2.19 (3H, s), 2.50 (2H, m),3.61 (2H, m), 3.83 (2H, m), 4.17 (1H, m), 4.36 (2H, q), 4.38 (2H, d),7.02-7.09 (3H, m), 8.17 (1H, s), 8.62 (1H, s), 8.93 (1H, t), 9.96 (1H,d): δ_(C) (D₆ DMSO) 14.65, 18.91, 19.33, 32.81, 41.06, 41.86, 48.57,64.94, 101.69, 102.18, 124.44, 128.22, 129.24, 133.28, 134.31, 135.78,136.91, 149.26, 149.59, 151.36, 168.81

Example 518AN-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidehydrochloride; also known as:N-(3,4-dimethylbenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidehydrochloride

A solution of Example 518 (1.3 g, 3.19 mmol) in anhydroustetrahydrofuran (200 ml) was treated with a solution of hydrogenchloride in dioxane (4M, 8 ml) and the mixture stirred at ambienttemperature for 16 hours. The resultant white precipitate was collectedby filtration and recrystallised from hot methanol (100 ml) to give thetitle compound Example 518A as a white crystalline solid (1.12 g, 79%).

LCMS showed MH⁺=408; T_(ret)=3.21 min. δ_(H) (D₆ DMSO) 1.39 (3H, t),1.59 (2H, m), 2.01 (2H, m), 2.19 (3H, s), 2.20 (3H, s), 3.64 (2H, t),3.83 (2H, m), 4.28 (1H, m), 4.40 (2H, d), 4.50 (2H, q), 7.04-7.11 (3H,m), 9.40 (1H, s (br)), 10.72 (1H, s (br)).

Example 6504-[({[1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoicacid sodium salt

2M-Sodium hydroxide solution (98 μL, 0.196 mmol) was added to a stirredsolution of Example 593 (22 mg, 0.049 mmol) in methanol (104 μL) andwater (6 μL). The resulting solution was stirred at 50° C. undernitrogen. After 16 h, the reaction mixture was diluted with water (0.5ml) and adjusted to pH 4 with acetic acid. The mixture was extractedwith ethyl acetate (2×0.5 ml), and the combined extracts were dried(Na₂SO₄) and evaporated in vacuo to give a solid (15 mg). This solid wassuspended in water (0.5 ml) and treated with 2M-sodium hydroxidesolution (15 μL). Evaporation of solvent in vacuo afforded Example 650as a white solid (11 mg). LCMS showed MH⁺=425; T_(RET)=2.69 min.

Example 6513-[({[1-Ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoicacid

2M-Sodium hydroxide solution (98 μL, 0.196 mmol) was added to a stirredsolution of Example 558 (22 mg, 0.049 mmol) in methanol (104 μL) andwater (6 μL). The resulting solution was stirred at 50° C. undernitrogen. After 16 h, the reaction mixture was diluted with water (0.5ml) and adjusted to pH 4 with acetic acid. The precipitated solid wascollected by filtration and dried in vacuo to afford Example 651 as awhite solid (15 mg). LCMS showed MH⁺=425; T_(RET)=2.72 min.

Example 652 Ethyl1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

A mixture of Example 205 (200 mg), hydroxylamine hydrochloride (50 mg)and anhydrous potassium carbonate (420 mg) in acetonitrile (10 ml) wasstirred and heated at reflux for 17 hours. The solution was cooled andconcentrated in vacuo. The residue was partitioned between EtOAc andwater. The organic phase was separated, dried over Na₂SO₄ andconcentrated in vacuo to give Example 652 as a white powder (203 mg).LCMS showed MH⁺=346; T_(RET)=2.84 min.

Example 6531-Ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A mixture of Example 263 (217 mg), hydroxylamine hydrochloride (43 mg)and anhydrous potassium carbonate (355 mg) in acetonitrile (10 ml) wasstirred and heated at reflux for 17 hours. The solution was cooled andconcentrated in vacuo. The residue was partitioned between EtOAc andwater. The organic phase was separated, dried over Na₂SO₄ andconcentrated in vacuo to give Example 653 as a yellow solid (186 mg).LCMS showed MH⁺=437; T_(RET)=2.82 min. δ_(H) (CDCl₃) 1.49 (3H, t), 1.80(2H, m), 2.2-2.4 (4H, m), 2.54 (1H, m), 3.13 (1H, dt), 3.81 (3H, s),4.13 (1H, m), 4.46 (2H, q), 4.54 (2H, d), 6.28 (1H, t), 6.90+7.28 (4H,AA′BB′), 7.98 (1H, s), 8.36 (1H, s), 9.84 (1H, d). Hydroxyl proton notvisible.

The following examples were prepared by a similar procedure, e.g. usingthe same or a similar number of moles of reagents and the same orsimilar volumes of solvents:

Source of Starting LC-MC Example No. NR⁴R⁵ HNR⁴R⁵ Material MH + ionRetention time 654

Aldrich Example 265 450 2.35 680

Salor; or ICN Biomedicals, Inc.; or Synthesis, 1982, 12, 1036 Example260 435 3.10 681

CHMSRVAS; or Matrix Scientific; or Chem. Ber., 1969, 102, 2770 Example261 435 3.08 682

Lancaster Example 677 475 3.20 683

Maybridge Chemical Company Ltd; or WO 01/30745 Example 678 455 3.17 684

Trans World Chemicals Inc.; or DE 1953059 Example 679 455 3.17 685

Fluorochem; or WO 98/45268 Example 266 473 3.00 686

Aldrich; or Meindl et al., J. Med. Chem., 1984, 27(9), 1111; or Org.Lett, 2002 4(12), 2055 Example 267 475 3.13

See later for alternative preparation of Example 681.

Example 6551-Ethyl-4-({4-[(ethyloxy)imino]cyclohexyl}amino)-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A mixture of Example 263 (25 mg), ethoxyamine hydrochloride (R²⁶ONH₂where R²⁶=Et, 20 mg) and diisopropylethylamine (30 mg) in acetonitrile(3 ml) was stirred and heated at reflux for 3.25 hours. The solution wascooled and concentrated in vacuo. The residue was applied to an SPEcartridge (5 g). The cartridge was eluted with EtOAc. Fractionscontaining the desired product were concentrated in vacuo to giveExample 655 as a colourless gum (20 mg). LCMS showed MH⁺=465;T_(RET)=3.28 min.

The following examples were prepared by a similar procedure, e.g. usingthe same or a similar number of moles of reagents and the same orsimilar volumes of solvents:

Example Source of Starting LC-MC No. R²⁶ R²⁶ONH₂ Material MH + ionRetention time 656 Me Aldrich Example 263 451 2.52 657 ^(t)Bu AldrichExample 263 493 3.66

Example 6581-Ethyl-N-{[4-(methyloxy)phenyl]methyl}-4-[(7-oxohexahydro-1H-azepin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A suspension of cyanuric chloride (2,4,6-trichloro-1,3,5-triazine) (I 50mg) in DMF (0.2 ml) was stirred for 30 minutes at room temperature. Thesuspension was diluted to 7 ml with DMF, with stirring. A 11.0 mlportion of the resultant suspension was removed and added to Example 653(52 mg). The resultant solution was stirred for 90 hours at roomtemperature, then concentrated in vacuo. The residue was partitionedbetween EtOAc and water. The organic phase was separated and washedconsecutively with saturated sodium carbonate, 10% w/v citric acid andsaturated brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was applied to an SPE cartridge (2 g). The cartridge was elutedsuccessively with EtOAc:cyclohexane (1:1), EtOAc and then a (100:8:1)mixture of dichloromethane, ethanol and ammonia. Fractions containingthe desired product (eluted in the ammoniacal solution) wereconcentrated in vacuo to give Example 658 as a colourless oil (11 mg).LCMS showed MH⁺=437; T_(RET)=2.50 min.

Example 659 Ethyl1-ethyl-4-[(7-oxohexahydro-1H-azepin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Example 659 was prepared from Example 652, using an identical procedureto that used for Example 658. LCMS showed MH⁺=346; T_(RET)=2.56 min.

Example 6604-{[cis-4-(Butylamino)cyclohexyl]amino}-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A solution of Example 258 (25 mg), butyraldehyde (5 mg) and glacialacetic acid (30 mg) in DCM (3 ml) was stirred for 10 min. Sodiumtriacetoxyborohydride (21 mg) was added. The reaction mixture wasstirred for 1.5 hours. Sodium bicarbonate (1.0 Molar, 3 ml) was addeddropwise, with stirring. After stirring for 5 min. the phases wereseparated. The organic phase was dried over Na₂SO₄ and applied to an SPEcartridge (5 g). The cartridge was eluted with a (100:8:1) mixture ofdichloromethane, ethanol and ammonia. Fractions containing the desiredproduct were concentrated in vacuo to give Example 660 as an amorphous,cream solid (19 mg). LCMS showed MH⁺=346; T_(RET)=2.56 min.

Examples 661 to 664

General Procedure:

Intermediate 17 (0.16 mmol) in acetonitrile (1 ml) was treated with theR³NH₂ amine (0.8 mmol) in acetonitrile (1 ml) andN,N-diisopropylethylamine (0.8 mmol). The mixture was heated at 50° C.for 18 h then concentrated in vacuo. The residue was diluted with water(3 ml) and extracted with dichloromethane (2×5 ml). The combined organicextracts were evaporated, and the residue was purified by mass directedautoprep HPLC to give the desired product containing formic acid. Thismaterial was dissolved in chloroform-methanol (10/1, 5.5 ml) and washedwith 5% sodium hydrogen carbonate solution (1 ml) to give afterevaporation of solvents the pure product. Example Source of StartingLC-MC No. NHR³ ** R³NH₂ Material MH + ion Retention time 214

J. Med. Chem., 1994, 37(17), 2360 Intermediate 17 393 2.16 661

Aldrich Intermediate 17 393 2.16 662

Aldrich Intermediate 17 393 2.29 663

Aldrich Intermediate 17 393 2.30 664

Peakdale Molecular Ltd Intermediate 17 393 2.21** For NHR³ in Examples 214 and 661-663, NHR³ is the cys or trans isomeras shown. For Examples 662-664, NHR³ is the 3-amino- or 2-amino-cycohex-1-ylamino group in a racemic form.

Example 665 Ethyl1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[cis-(3-hydroxycyclohex-1-yl)amino group, racemic]

3-Aminocyclohexanol (0.677 g, 5.9 mmol, as described in J. Chem. Soc.,Perkin Trans 1, 1994, 537) in acetonitrile (10 ml) and ethanol (1 ml)was added at room temperature to a stirred solution of Intermediate 1(1.24 g, 4.9 mmol) and diisopropylethylamine (4.26 ml, 24.5 mmol) inacetonitrile (25 ml). The resulting mixture was stirred at 85° C. for 17h. The mixture was concentrated in vacuo, and the residue waspartitioned between DCM (50 ml) and water (10 ml). The phases wereseparated and the organic phase was dried (Na₂SO₄) and evaporated togive an orange-brown oil. The oil was purified by Biotage chromatography(silica 100 g) eluting with 30-50% EtOAc in cyclohexane to give Example665 as a white foam (0.681 g). LCMS showed MH⁺=333; T_(RET)=2.76 min.

Examples 666-676

[cis-(3-hydroxycyclohex-1-yl)amino group, racemic]

General Procedure:

A mixture of Intermediate 76 (0.1 mmol), HATU (0.1 mmol) and DIPEA (0.4mmol) in DMF (0.5 ml) was shaken at room temperature for 10 min. Asolution of the amine HNR⁴R⁵ (0.12 mmol) in DMF (0.5 ml) was then addedand the mixture agitated for several minutes to give a solution. Thesolution was stored at room temperature for 16 h, then concentrated invacuo. The residue was purified by mass directed autoprep HPLC. ExampleSource of Starting LC-MC No. NR⁴R⁵ HNR⁴R₅ Material MH + ion Retentiontime 666

Aldrich Intermediate 76 332 2.35 667

Aldrich Intermediate 76 398 2.96 668

Manchester Organics Ltd Intermediate 76 393 2.29 669

Aldrich Intermediate 76 412 2.88 670

Acros Intermediate 76 472 2.57 671

Aldrich Intermediate 76 454 2.67 672

Aldrich Intermediate 76 395 2.15 673

N.D. Zelinsky Institute Intermediate 76 398 2.35 674

Matrix Scientific; or Chem. Ber., 1969, 102, 2770 Intermediate 76 4223.08 669

Aldrich Intermediate 76 424 2.81 669

ICN Biomedicals, Inc.; or Salor; or Synthesis, 1982, 12, 1036Intermediate 76 422 3.08

Example 260 Alternative ProcedureN-[(2,4-dimethylphenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

Alternative procedure for preparing Example 260:

A solution of Intermediate 58 (45 mg), HATU (63 mg) and DIPEA (39 mg) inacetonitrile (5 ml) was stirred for 10 min. A solution of2,4-dimethylbenzylamine (24 mg) (available from Salor; or ICNBiomedicals, Inc.; or Synthesis, 1982, 12, 1036) in acetonitrile (1 ml)was added. The reaction mixture was stirred for 18 h. The solution wasconcentrated and the residue partitioned between ethyl acetate (25 ml)and 0.5M sodium bicarbonate (20 ml). The organic phase was separated,washed with water (20 ml), dried over Na₂SO₄ and concentrated to leave agum which was applied to an SPE cartridge (5 g). The cartridge waseluted with ethyl acetate. Fractions containing the desired compoundwere combined and concentrated in vacuo to give Example 260 (32 mg).LC-MS showed MH⁺=420; T_(RET)=3.16 min. δ_(H) (CDCl₃): 1.49 (3H, t),2.11 (2H, m), 2.33 (3H, s), 2.35 (3H, s), 2.40 (2H, m), 2.52 (2H, m),2.61 (2H, m), 4.36 (1H, m), 4.47 (2H, q), 4.55 (2H, d), 6.14 (1H, t),7.01+7.18 (2H, AA′BB′), 7.04 (1H, s), 8.01 (1H, s), 8.36 (1H, s), 9.96(1H, d).

The following Examples 677-679 were prepared in a similar manner toExample 260 (alternative procedure above), for example using the same ora similar number of moles of reagents and the same or similar volumes ofsolvents: Example Source of Starting LC-MC No. NR⁴R⁵ HNR⁴R₅ MaterialMH + ion Retention time 677

Lancaster Intermediate 58 460 3.28 678

Maybridge Chemical Company Ltd.; or WO 01/30745 Intermediate 58 440 3.25679

Trans World Chemicals, Inc.; or DE 1953059 Intermediate 58 440 3.24

Examples 680-686 and their preparation are shown above together withExample 653.

Alternative Preparation of Example 681:N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

A mixture of Example 261 (35 mg), hydroxylamine hydrochloride (10 mg)and diisopropylethylamine (26 mg) in acetonitrile (4 ml) was stirred andheated at reflux for 2.5 hours. The solution was cooled and concentratedin vacuo. The residue was partitioned between EtOAc and water. Theorganic phase was separated, dried over Na₂SO₄ and concentrated invacuo. The residue was applied to an SPE cartridge (10 g). The cartridgewas eluted with EtOAc:cyclohexane (1:1) and then EtOAc. Fractionscontaining the desired compound were combined and concentrated in vacuoto give Example 681 as a white, amorphous solid (18 mg). LCMS showedMH⁺=435; T_(RET)=3.08 min. δ_(H) (CDCl₃) 1.49 (3H, t), 1.79 (2H, m),2.24 (6H, s), 2.19-2.38 (4H, m), 2.56 (2H, dt), 4.13 (1H, m), 4.46 (2H,q), 4.53 (2H, d), 6.36 (1H, t), 7.09 (2H, t), 7.12 (1H, s), 7.98 (1H,s), 8.38 (1H, s), 9.79 (1H, d). Hydroxyl proton not visible.

1. A compound of formula (I) or a salt thereof:

wherein: R¹ is C₁₋₄alkyl, C₁₋₃fluoroalkyl, —CH₂CH₂OH or—CH₂CH₂CO₂C₁₋₂alkyl; R² is a hydrogen atom (H), methyl or C₁fluoroalkyl;R³ is optionally substituted C₃₋₈cycloalkyl or optionally substitutedmono-unsaturated-C₅₋₇cycloalkenyl or an optionally substitutedheterocyclic group of sub-formula (aa), (bb) or (cc);

in which n¹ and n² independently are 1 or 2; and in which Y is O, S,SO₂, or NR¹⁰; where R¹⁰ is a hydrogen atom (H), C₁₋₄alkyl,C₁₋₂fluoroalkyl, CH₂C(O)NH₂, C(O)NH₂, C(O)—C₁₋₂alkyl, C(O)—C₁fluoroalkylor —C(O)—CH₂O—C₁₋₂alkyl; and wherein in R³ the C₃₋₈cycloalkyl or theheterocyclic group of sub-formula (aa), (bb) or (cc) is optionallysubstituted with one or two substituents independently being oxo (═O);OH; C₁₋₂alkoxy; C₁₋₂fluoroalkoxy; NHR²¹ wherein R²¹ is a hydrogen atom(H) or C₁₋₅ straight-chain alkyl; C₁₋₂alkyl; C₁₋₂fluoroalkyl; —CH₂OH;—CH₂CH₂OH; —CH₂NHR²² wherein R²² is H or C₁₋₂alkyl; —C(O)OR²³ whereinR²³ is H or C₁₋₂alkyl; —C(O)NHR²⁴ wherein R²⁴ is H or C₁₋₂alkyl;—C(O)R²⁵ wherein R²⁵ is C₁₋₂alkyl; fluoro; hydroxyimino (═N—OH); or(C₁₋₄alkoxy)imino (═N—OR²⁶ where R²⁶ is C₁₋₄alkyl); and wherein any OH,alkoxy, fluoroalkoxy or NHR²¹ substituent is not substituted at the R³ring carbon attached (bonded) to the —NH— group of formula (I) and isnot substituted at either R³ ring carbon bonded to the Y group of theheterocyclic group (aa), (bb) or (cc); and wherein, when R³ isoptionally substituted mono-unsaturated-C₅₋₇cycloalkenyl, then thecycloalkenyl is optionally substituted with one or two substituentsbeing fluoro or C₁₋₂alkyl provided that if there are two substituentsthen they are not both C₂alkyl, and the R³ ring carbon bonded to the—NH— group of formula (I) does not partake in the cycloalkenyl doublebond; or R³ is a bicyclic group of sub-formula (dd):

or of sub-formula (ee):

wherein Y¹, Y² and Y³ independently are CH₂ or oxygen (O) provided thatno more than one of Y¹, Y² and Y³ is oxygen (O); X is NR⁴R⁵ or OR^(5a),in which: R⁴ is a hydrogen atom (H); C₁₋₆alkyl; C₁₋₃fluoroalkyl; orC₂₋₆alkyl substituted by one substituent R¹¹; and R⁵ is a hydrogen atom(H); C₁₋₈alkyl; C₁₋₈ fluoroalkyl; C₃₋₈cycloalkyl optionally substitutedby a C₁₋₂alkyl group; or —(CH₂)_(n) ⁴—C₃₋₈cycloalkyl optionallysubstituted, in the —(CH₂)_(n) ⁴— moiety or in the C₃₋₈cycloalkylmoiety, by a C₁₋₂alkyl group, wherein n⁴ is 1, 2 or 3; or R⁵ isC₂₋₆alkyl substituted by one or two independent substituents R¹¹;wherein each substituent R¹¹, independently of any other R¹¹ substituentpresent, is: hydroxy (OH); C₁₋₆alkoxy; phenyloxy; benzyloxy; —NR¹²R¹³;—NR¹⁵—C(O)R¹⁶; —NR¹⁵—C(O)—O—R¹⁶; —NR¹⁵—C(O)—NH—R¹⁵; or —NR¹⁵—SO₂R¹⁶; andwherein any R¹¹ substituent which is OH, alkoxy or —NR¹²R¹³ is notsubstituted at any carbon atom, of any R⁴ or R⁵ substituted alkyl, whichis bonded to the nitrogen of NR⁴R⁵; or R⁵ is —(CH₂)_(n) ¹¹—C(O)R¹⁶;—(CH₂)_(n) ¹²—C(O)NR¹²R¹³; —CHR¹⁹—C(O)NR¹²R¹³; —(CH₂)_(n) ¹²—C(O)OR¹⁶;—(CH₂)_(n) ¹²—C(O)OH; —CHR¹⁹—C(O)OR¹⁶; —CHR¹⁹—C(O)OH; —(CH₂)_(n)¹²—SO₂—NR¹²R¹³; —(CH₂)_(n) ¹²—SO₂R¹⁶; or —(CH₂)_(n) ¹²—CN; wherein n¹¹is 0, 1, 2, 3 or 4 and n¹² is 1, 2, 3 or 4; or R⁵ is —(CH₂)_(n) ¹³—Hetwherein n¹³ is 0, 1, 2, 3 or 4 and Het is a 4-, 5-, 6- or 7-memberedsaturated or partly-saturated heterocyclic ring containing one or tworing-hetero-atoms independently selected from O, S, and N; wherein anyring-hetero-atoms present are not bound to the —(CH₂)_(n) ¹³— moietywhen n¹³ is 1 and are not bound to the nitrogen of NR⁴R⁵ when n¹³ is 0;wherein any ring-nitrogens which are present and which are notunsaturated are present as NR¹⁷ where R¹⁷ is as defined herein; andwherein one or two of the carbon ring-atoms independently are optionallysubstituted by C₁₋₂alkyl; or R⁵ is phenyl optionally substituted with,independently, one, two or three of: a halogen atom; C₁₋₆alkyl;C₁₋₂fluoroalkyl; C₁₋₄alkoxy; C₁₋₂fluoroalkoxy; C₃₋₆cycloalkyloxy;—C(O)R^(16a); —C(O)OR³⁰; —S(O)₂—R^(16a); R^(16a)—S(O)₂—NR^(15a)—;R⁷R⁸N—S(O)₂—; C₁₋₂alkyl-C(O)—R^(15a)N—S(O)₂—; C₁₋₄alkyl-S(O)—; Ph—S(O)—;R⁷R⁸N—CO—; —NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH; C₁₋₄alkoxymethyl; C₁₋₄alkoxyethyl;C₁₋₂alkyl-S(O)₂—CH₂—; R⁷R⁸N—S(O)₂—CH₂—; C₁₋₂alkyl-S(O)₂—NR^(15a)—CH₂—;—CH₂—OH; —CH₂CH₂—OH; —CH₂—NR⁷R⁸; —CH₂—CH₂—NR⁷R⁸; —CH₂—C(O)OR³⁰;—CH₂—C(O)—NR⁷R⁸; —CH₂—NR^(15a)—C(O)—C₁₋₃alkyl; —(CH₂)_(n) ¹⁴—Het¹ wheren¹⁴ is 0 or 1; cyano (CN); Ar^(5a); or phenyl, pyridinyl or pyrimidinylwherein the phenyl, pyridinyl or pyrimidinyl independently areoptionally substituted by one or two of fluoro, chloro, C₁₋₂alkyl,C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; or where two adjacentsubstituents, on the R⁵ optionally substituted phenyl, taken togetherare —O—(CMe₂)—O— or —O—(CH₂)_(n) ¹⁴—O— where n¹⁴ is 1 or 2; wherein R⁷and R⁸ are independently a hydrogen atom (H); C₁₋₄alkyl; C₃₋₆cycloalkyl;or phenyl optionally substituted by one or two of: fluoro, chloro,C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; or R⁷ and R⁸together are —(CH₂)_(n) ⁶— or —C(O)—(CH₂)_(n) ⁷— or —C(O)—(CH₂)_(n)⁷—C(O)— or —(CH₂)_(n) ⁸—X⁷—(CH₂)_(n) ⁹— or —C(O)—X⁷—(CH₂)_(n) ¹⁰— inwhich: n⁶ is 3, 4, 5 or 6, n⁷ is 2, 3, 4, or 5, n⁸ and n⁹ and n¹⁰independently are 2 or 3, and X⁷ is O or NR¹⁴ wherein R¹⁴ is H,C₁₋₂alkyl or C(O)Me; or R⁵ has the sub-formula (x), (y), (y1) or (z):

wherein in sub-formula (x), n=0, 1 or 2; in sub-formula (y) and (y1),m=1 or 2; and in sub-formula (z), r=0, 1 or 2; wherein in sub-formula(x) and (y) and (y1), none, one or two of A, B, D, E and F areindependently nitrogen or nitrogen-oxide (N⁺—O⁻) provided that no morethan one of A, B, D, E and F is nitrogen-oxide; and the remaining of A,B, D, E and F are independently CH or CR⁶; provided that when n is 0 insub-formula (x) then one or two of A, B, D, E and F are independentlynitrogen or nitrogen-oxide (N⁺—O⁻) and no more than one of A, B, D, Eand F is nitrogen-oxide; wherein, each R⁶, independently of any other R⁶present, is: a halogen atom; C₁₋₆alkyl; C₁₋₄fluoroalkyl; C₁₋₄alkoxy;C₁₋₂fluoroalkoxy; C₃₋₆cycloalkyloxy; —C(O)R^(16a); —C(O)OR³⁰;—S(O)₂—R^(16a); R^(16a)—S(O)₂—NR^(15a); R⁷R⁸N—S(O)₂—;C₁₋₂alkyl-C(O)—R^(15a)N—S(O)₂—; C₁₋₄alkyl-S(O)—; Ph—S(O)—; R⁷R⁸N—CO—;—NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH; C₁₋₄alkoxymethyl; C₁₋₄alkoxyethyl;C₁₋₂alkyl-S(O)₂—CH₂—; R⁷R⁸N—S(O)₂—CH₂—; C₁₋₂alkyl-S(O)₂—NR^(15a)—CH₂—;—CH₂—OH; —CH₂CH₂—OH; —CH₂—NR⁷R⁸; —CH₂—CH₂—NR⁷R⁸; —CH₂—C(O)OR³⁰;—CH₂—C(O)—NR⁷R⁸; —CH₂—NR^(15a)—C(O)—C₁₋₃alkyl; —(CH₂)_(n) ¹⁴—Het¹ wheren¹⁴ is 0 or 1; cyano (CN); Ar^(5b); or phenyl, pyridinyl or pyrimidinylwherein the phenyl, pyridinyl or pyrimidinyl independently areoptionally substituted by one or two of fluoro, chloro, C₁₋₂alkyl,C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; or where two adjacent R⁶taken together are —O—(CMe₂)—O— or —O——(CH₂)_(n) ¹⁴—O— where n¹⁴ is 1 or2; wherein R⁷ and R⁸ are as herein defined; wherein sub-formula (y) and(y1), independently, are optionally substituted by oxo (═O) at a ringcarbon adjacent the 6-membered aromatic ring; wherein in sub-formula(z), G is O or S or NR⁹ wherein R⁹ is a hydrogen atom (H), C₁₋₄alkyl orC₁₋₄fluoroalkyl; none, one, two or three of J, L, M and Q are nitrogen;and the remaining of J, L, M and Q are independently CH or CR⁶ where R⁶,independently of any other R⁶ present, is as defined herein; or R⁴ andR⁵ taken together are —(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²— or —(CH₂)_(p)³—X⁵—(CH₂)_(p) ⁴— or —C(O)—X⁵—(CH₂)_(p) ⁵—, in which: p¹=3, 4, 5 or 6,p² is 2, 3, 4, or 5, and p³ and p⁴ and p⁵ independently are 2 or 3 andX⁵ is O or NR¹⁷; and wherein, when R⁴ and R⁵ taken together are—(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²—, the NR⁴R⁵ heterocycle is optionallysubstituted by one R¹⁸ substituent wherein R¹⁸ is: C₁₋₄alkyl;C₁₋₂fluoroalkyl; C₃₋₆cycloalkyl; C₁₋₂alkoxy (not substituted at aring-carbon bonded to the NR⁴R⁵ ring-nitrogen); C₁fluoroalkoxy (notsubstituted at a ring-carbon bonded to the NR⁴R⁵ ring-nitrogen); OH (notsubstituted at a ring-carbon bonded to the NR⁴R⁵ ring-nitrogen);—(CH₂)_(p) ⁷—C(O)R¹⁶ wherein p⁷ is 0, 1, 2 or 3; —(CH₂)_(p) ⁷—C(O)OR¹⁶;—(CH₂)_(p) ⁷—OC(O)R¹⁶; —(CH₂)_(p) ⁷—C(O)NR¹²R¹³; —(CH₂)_(p)⁷—NR¹⁵C(O)R¹⁶; —(CH₂)_(p) ⁷—NR¹⁵C(O)NR¹²R¹³; —(CH₂)_(p) ⁷—NR¹⁵C(O)OR¹⁶;—(CH₂)_(p) ⁷—SO₂R¹⁶; —(CH₂)_(p) ⁷—SO₂ NR¹²R¹³; —(CH₂)_(p) ⁷—NR¹⁵SO₂R¹⁶;—(CH₂)_(p) ⁷—OH; —(CH₂)_(p) ⁷—OR¹⁶; or phenyl optionally substituted byone or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy orC₁fluoroalkoxy; or R⁴ and R⁵ taken together are —(CH₂)_(p) ¹— or—C(O)—(CH₂)_(p) ²— or —(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴— or —C(O)—X⁵—(CH₂)_(p)⁵— as defined herein, and wherein the NR⁴R⁵ heterocycle is fused to aphenyl ring optionally substituted on the phenyl by one or two of: ahalogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy;and R^(5a) is C₁₋₈alkyl; C₁₋₈ fluoroalkyl; C₃₋₈cycloalkyl; —(CH₂)_(n)^(4a)—C₃₋₆cycloalkyl wherein n^(4a) is 1 or 2; phenyl optionallysubstituted with one or two of: a halogen atom, C₁₋₂alkyl,trifluoromethyl, C₁₋₂alkoxy or trifluoromethoxy; or R^(5a) has thesub-formula (x), (y), (y1) or (z) as defined herein; R¹² and R¹³independently are H; C₁₋₅alkyl; C₃₋₆cycloalkyl; or phenyl optionallysubstituted by one or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl,C₁₋₂alkoxy or C₁fluoroalkoxy; or R¹² and R¹³ together are —(CH₂)_(n) ⁶—or —C(O)—(CH₂)_(n) ⁷— or —C(O)—(CH₂)_(n) ⁷—C(O)— or —(CH₂)_(n)⁸—X¹²—(CH₂)_(n) ⁹— or —C(O)—X¹²—(CH₂)_(n) ¹⁰— in which: n⁶ is 3, 4, 5 or6, n⁷ is 2, 3, 4, or 5, n⁸ and n⁹ and n¹⁰ independently are 2 or 3 andX¹² is O or NR^(14a) wherein R^(14a) is H, C₁₋₂alkyl or C(O)Me; R¹⁵ is ahydrogen atom (H); C₁₋₄alkyl; C₃₋₆cycloalkyl; or phenyl optionallysubstituted by one or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl,C₁₋₂alkoxy or C₁fluoroalkoxy; R^(15a), independent of other R^(15a), isa hydrogen atom (H) or C₁₋₄alkyl; R¹⁶ and R^(16a) independently are:C₁₋₆alkyl; C₃₋₆cycloalkyl optionally substituted by one oxo (═O), OH orC₁₋₂alkyl substituent; C₃₋₆cycloalkyl-CH₂—; pyridinyl optionallysubstituted on a ring carbon atom by one of: a halogen atom, C₁₋₂alkyl,C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; Ar^(5c); phenyl optionallysubstituted by one or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl,C₁₋₂alkoxy or C₁fluoroalkoxy; benzyl optionally substituted at anaromatic carbon atom by one or two of: a halogen atom, C₁₋₂alkyl,C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; or a 4-, 5-, 6- or7-membered saturated heterocyclic ring connected at a ring-carbon andcontaining one or two ring-hetero-atoms independently selected from O,S, and N; wherein any ring-nitrogens which are present are present asNR²⁷ where R²⁷ is H, C₁₋₂alkyl or —C(O)Me; and wherein the ring isoptionally substituted at carbon by one C₁₋₂alkyl or oxo (═O)substituent, provided that any oxo (═O) substituent is substituted at aring-carbon atom bonded to a ring-nitrogen; wherein Ar^(5a), Ar^(5b) andAr^(5c) independently is/are a 5-membered aromatic heterocyclic ringcontaining one O, S or NR^(15a) in the 5-membered ring, wherein the5-membered ring can optionally additionally contain one or two N atoms,and wherein the heterocyclic ring is optionally substituted on a ringcarbon atom by one of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl, —CH₂OH,—CH₂—OC₁₋₂alkyl, OH (including the keto tautomer thereof) or—CH₂—NR²⁸R²⁹ wherein R²⁸ and R²⁹ independently are H or methyl; and R¹⁷is a hydrogen atom (H); C₁₋₄alkyl; C₁₋₂fluoroalkyl; C₃₋₆cycloalkyl;—(CH₂)_(p) ⁶—C(O)R¹⁶ wherein p⁶ is 0, 1, 2 or 3; —(CH₂)_(p)⁶—C(O)NR¹²R¹³; —(CH₂)_(p) ⁶—C(O)OR¹⁶; —(CH₂)_(p) ⁶—C(O)OH; —SO₂R¹⁶;—C(O)—CH₂—NR¹²R¹³; —C(O)—CH₂—NR^(15a)—C(O)—C₁₋₃alkyl;—C(O)—CH₂—O—C₁₋₃alkyl; or phenyl or benzyl wherein the phenyl or benzylis optionally substituted at an aromatic carbon atom by one or two of: ahalogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy;R¹⁹ is C₁₋₄alkyl; —(CH₂)_(n) ²⁰—OR²⁰ wherein n²⁰ is 1, 2, 3 or 4 and R²⁰is a hydrogen atom (H) or C₁₋₄alkyl; —CH(Me)-OH; —CH₂—SH; —CH₂—CH₂—S-Me;benzyl; or (4-hydroxyphenyl)methyl; and R³⁰, independent of other R³⁰,is a hydrogen atom (H), C₁₋₄alkyl or C₃₋₆cycloalkyl; and Het¹,independent of other Het¹, is a 4-, 5-, 6- or 7-membered saturatedheterocyclic ring connected at a ring-carbon and containing one or tworing-hetero-atoms independently selected from O, S, and N; wherein anyring-nitrogens which are present are present as NR³¹ where R³¹ is H,C₁₋₂alkyl or —C(O)Me; and wherein the ring is optionally substituted atcarbon by one C₁₋₂alkyl or oxo (═O) substituent, provided that any oxo(═O) substituent is substituted at a ring-carbon atom bonded to aring-nitrogen; provided that: when R³ is the heterocyclic group ofsub-formula (bb), n¹ is 1, and Y is NR¹⁰, then: either (a) R¹⁰ is notC₁₋₄alkyl, C₁₋₂fluoroalkyl or CH₂C(O)NH₂; or (b) R¹⁰ is methyl and thecompound is:1-ethyl-N-(2-ethylbutyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamideor1-ethyl-N-(4-fluorophenyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;and provided that: where X is OR^(5a), the compound is other than thecompound wherein R¹ is methyl, X is OEt, and R³ is cyclopentyl.
 2. Acompound according to claim 1 comprising formula (IA) or a salt thereof:

wherein: X is NR⁴R⁵ or OR^(5a), in which: R⁴ is hydrogen, C₁₋₂alkyl orC₁₋₂fluoroalkyl, and R⁵ is hydrogen, C₁₋₈alkyl, C₁₋₈ fluoroalkyl, orC₃₋₈cycloalkyl, phenyl optionally substituted with one or two of: ahalogen atom, C₁₋₂alkyl, trifluoromethyl, C₁₋₂alkoxy ortrifluoromethoxy; or R⁵ has the sub-formula (x), (y) or (z):

wherein in sub-formula (x) and (z), n=1 or 2; and in sub-formula (y),m=1 or 2; wherein in sub-formula (x) and (y), none, one or two of A, B,D, E and F are nitrogen; and the remaining of A, B, D, E and F are CH orCR⁶ where R⁶ is a halogen atom, C₁₋₄alkyl, C₁₋₄fluoroalkyl, C₁₋₂alkoxy,C₁₋₂fluoroalkoxy, C₁₋₂alkylsulphonyl (C₁₋₂alkyl-SO₂—),C₁₋₂alkyl-SO₂—NH—, R⁷R⁸N—SO₂—, R⁷R⁸N—CO—, R⁷R⁸N, OH, C₁₋₄alkoxymethyl,or C₁₋₂alkyl-SO₂—CH₂—, wherein R⁷ and R⁸ are independently hydrogen orC₁₋₂alkyl; wherein in sub-formula (z), G is O or S or NR⁹ wherein R⁹ isC₁₋₄alkyl or C₁₋₄fluoroalkyl; none, one or two of J, L, M and Q arenitrogen; and the remaining of J, L, M and Q are CH or CR⁶ where R⁶ isas defined herein; or R⁴ and R⁵ taken together are —(CH₂)_(p)— wherep=3, 4 or 5; R^(5a) is C₁₋₈alkyl; C₁₋₈ fluoroalkyl; C₃₋₈cycloalkyl;phenyl optionally substituted with one or two of: a halogen atom,C₁₋₂alkyl, trifluoromethyl, C₁₋₂alkoxy or trifluoromethoxy; or R^(5a)has the sub-formula (x), (y) or (z) as defined herein; R³ isC₃₋₈cycloalkyl or a heterocyclic group being

in which Y is O, S, SO₂, or NR¹⁰; where R¹⁰ is hydrogen, C₁₋₄alkyl,C₁₋₂fluoroalkyl, C(O)—C₁₋₂alkyl, or C(O)—CF₃; and wherein in R³ theC₃₋₈cycloalkyl or heterocyclic group is optionally substituted with oneor two substituents being OH, C₁₋₂alkoxy, trimethoxy, or C₁₋₂alkylgroup; and wherein any OH, alkoxy or trimethoxy substituent is notsubstituted at the ring carbon attached to the —NH— group of formula(IA) and is not substituted at either ring carbon bonded to the Y groupof the heterocyclic group; and R¹═C₁₋₄alkyl or C₁₋₂fluoroalkyl; providedthat: when R³ is the heterocyclic group being

and Y is NR¹⁰, then: either (a) R¹⁰ is hydrogen, C(O)—C₁₋₂alkyl, orC(O)—CF₃; or (b) R¹⁰ is methyl and the compound is:1-ethyl-N-(2-ethylbutyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamideor1-ethyl-N-(4-fluorophenyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;and provided that: where X is OR^(5a), the compound is other than thecompound wherein R¹ is methyl, X is OEt, and R³ is cyclopentyl.
 3. Acompound according to claim 1 comprising formula (IB) or a salt thereof:

wherein: R¹ is C₁₋₄alkyl, C₁₋₃fluoroalkyl, —CH₂CH₂OH or—CH₂CH₂CO₂C₁₋₂alkyl; R² is a hydrogen atom (H), methyl or C₁fluoroalkyl;R³ is optionally substituted C₃₋₈cycloalkyl or an optionally substitutedheterocyclic group of sub-formula (aa), (bb) or (cc);

in which n¹ and n² independently are 1 or 2; and in which Y is O, S,SO₂, or NR¹⁰; where R¹⁰ is a hydrogen atom (H), C₁₋₄alkyl,C₁₋₂fluoroalkyl, CH₂C(O)NH₂, C(O)NH₂, C(O)—C₁₋₂alkyl, or C(O)—C₁fluoroalkyl; and wherein in R³ the C₃₋₈cycloalkyl or the heterocyclicgroup of sub-formula (aa), (bb) or (cc) is optionally substituted withone or two substituents being oxo (═O), OH, C₁₋₂alkoxy,C₁₋₂fluoroalkoxy, or C₁₋₂alkyl; and wherein any OH, alkoxy orfluoroalkoxy substituent is not substituted at the R³ ring carbonattached (bonded) to the —NH— group of formula (IB) and is notsubstituted at either R³ ring carbon bonded to the Y group of theheterocyclic group (aa), (bb) or (cc); X is NR⁴R⁵ or OR^(5a), in which:R⁴ is a hydrogen atom (H); C₁₋₆alkyl; C₁₋₃fluoroalkyl; or C₂₋₆alkylsubstituted by one substituent R¹¹; and R⁵ is a hydrogen atom (H);C₁₋₈alkyl; C₁₋₈ fluoroalkyl; C₃₋₈cycloalkyl optionally substituted by aC₁₋₂alkyl group; or —(CH₂)_(n) ⁴—C₃₋₈cycloalkyl optionally substituted,in the —(CH₂)_(n) ⁴— moiety or in the C₃₋₈cycloalkyl moiety, by aC₁₋₂alkyl group, wherein n⁴ is 1, 2 or 3; or R⁵ is C₂₋₆alkyl substitutedby one or two independent substituents R¹¹; wherein each substituentR¹¹, independently of any other R¹¹ substituent present, is: hydroxy(OH); C₁₋₆alkoxy; phenyloxy; benzyloxy; —NR¹²R¹³; —NR¹⁵—C(O)R¹⁶;—NR¹⁵—C(O)—O—R¹⁶; —NR¹⁵—C(O)—NH—R¹⁵; or —NR¹⁵—SO₂R¹⁶; and wherein anyR¹¹ substituent which is OH, alkoxy or —NR¹²R¹³ is not substituted atany carbon atom, of any R⁴ or R⁵ substituted alkyl, which is bonded tothe nitrogen of NR⁴R⁵; or R⁵ is —(CH₂)_(n) ¹¹—C(O)R¹⁶; —(CH₂)_(n)¹¹—C(O)NR¹²R¹³; —CHR¹⁹—C(O)NR¹²R¹³; —(CH₂)_(n) ¹²—C(O)OR¹⁶;—CHR¹⁹—C(O)OR¹⁶; —(CH₂)_(n) ¹²—SO₂—NR¹²R¹³; —(CH₂)_(n) ¹²—SO₂R¹⁶; or—(CH₂)_(n) ¹²—CN; wherein n¹ is 0, 1, 2, 3 or 4 and n¹² is 1, 2, 3 or 4;or R⁵ is —(CH₂)_(n) ¹³—Het wherein n¹³ is 0, 1, 2, 3 or 4 and Het is a4-, 5-, 6- or 7-membered saturated or partly-saturated heterocyclic ringcontaining one or two ring-hetero-atoms independently selected from O,S, and N; wherein any ring-hetero-atoms present are not bound to the—(CH₂)_(n) ¹³— moiety when n¹³ is 1 and are not bound to the nitrogen ofNR⁴R⁵ when n¹³ is 0; wherein any ring-nitrogens which are present andwhich are not unsaturated are present as NR¹⁷ where R¹⁷ is as definedherein; and wherein one or two of the carbon ring-atoms independentlyare optionally substituted by C₁₋₂alkyl; or R⁵ is phenyl optionallysubstituted with one or two of: a halogen atom; C₁₋₄alkyl;C₁₋₂fluoroalkyl; C₁₋₄alkoxy; C₁₋₂fluoroalkoxy; C₁₋₂alkylsulphonyl(C₁₋₂alkyl-SO₂—); C₁₋₂alkyl-SO₂—NH—; R⁷R⁸N—SO₂—; R⁷R⁸N—CO—;—NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH; C₁₋₄alkoxymethyl; C₁₋₄alkoxyethyl;C₁₋₂alkyl-SO₂—CH₂—; cyano (CN); or phenyl optionally substituted by oneor two of fluoro, chloro, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy orC₁fluoroalkoxy; wherein R⁷ and R⁸ are independently a hydrogen atom (H);C₁₋₄alkyl; C₃₋₆cycloalkyl; or phenyl optionally substituted by one ortwo of: fluoro, chloro, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy orC₁fluoroalkoxy; or R⁷ and R⁸ together are —(CH₂)_(n) ⁶— or—C(O)—(CH₂)_(n) ⁷— or —C(O)—(CH₂)_(n) ⁷—C(O)— or —(CH₂)_(n)⁸—X⁷—(CH₂)_(n) ⁹— or —C(O)—X⁷—(CH₂)_(n) ¹⁰— in which: n⁶ is 3, 4, 5 or6, n⁷ is 2, 3, 4, or 5, n⁸ and n⁹ and n¹⁰ independently are 2 or 3, andX⁷ is O or NR¹⁴ wherein R¹⁴ is H or C₁₋₂alkyl; or R⁵ has the sub-formula(x), (y) or (z):

wherein in sub-formula (x), n=1 or 2; in sub-formula (y), m=1 or 2; andin sub-formula (z), r=0, 1 or 2; wherein in sub-formula (x) and (y),none, one or two of A, B, D, E and F are nitrogen; and the remaining ofA, B, D, E and F are independently CH or CR⁶; where R⁶ is a halogenatom; C₁₋₄alkyl; C₁₋₄fluoroalkyl; C₁₋₄alkoxy; C₁₋₂fluoroalkoxy;C₁₋₂alkylsulphonyl (C₁₋₂alkyl-SO₂—); C₁₋₂alkyl-SO₂—NH—; R⁷R⁸N—SO₂—;R⁷R⁸N—CO—; —NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH; C₁₋₄alkoxymethyl; C₁₋₄alkoxyethyl;C₁₋₂alkyl-SO₂—CH₂—; cyano (CN); or phenyl optionally substituted by oneor two of fluoro, chloro, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy orC₁fluoroalkoxy; wherein R⁷ and R⁸ are as herein defined; wherein insub-formula (z), G is O or S or NR⁹ wherein R⁹ is a hydrogen atom (H),C₁₋₄alkyl or C₁₋₄fluoroalkyl; none, one, two or three of J, L, M and Qare nitrogen; and the remaining of J, L, M and Q are independently CH orCR⁶ where R⁶ is as defined herein; or R⁴ and R⁵ taken together are—(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²— or —(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴— or—C(O)—X⁵—(CH₂)_(p) ⁵—, in which: p¹=3, 4, 5 or 6, p² is 2, 3, 4, or 5,and p³ and p⁴ and p⁵ independently are 2 or 3 and X⁵ is O or NR¹⁷;wherein R¹⁷ is a hydrogen atom (H); C₁₋₄alkyl; C₁₋₂fluoroalkyl;C₃₋₆cycloalkyl; —(CH₂)_(p) ⁶—C(O)R¹⁶ wherein p⁶ is 0, 1, 2 or 3;—(CH₂)_(p) ⁶—C(O)NR¹²R¹³; —(CH₂)_(p) ⁶—C(O)OR¹⁶; —SO₂R¹⁶; or phenyl orbenzyl wherein the phenyl or benzyl is optionally substituted at anaromatic carbon atom by one or two of: a halogen atom, C₁₋₂alkyl,C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; and wherein, when R⁴ and R⁵taken together are —(CH₂)_(p) ¹— or —C(O)—(CH₂)_(p) ²—, the NR⁴R⁵heterocycle is optionally substituted by one R¹⁸ substituent wherein R¹⁸is: C₁₋₄alkyl; C₁₋₂fluoroalkyl; C₃₋₆cycloalkyl; C₁₋₂alkoxy (notsubstituted at a ring-carbon bonded to the NR⁴R⁵ ring-nitrogen);C₁fluoroalkoxy (not substituted at a ring-carbon bonded to the NR⁴R⁵ring-nitrogen); OH (not substituted at a ring-carbon bonded to the NR⁴R⁵ring-nitrogen); —(CH₂)_(p) ⁷—C(O)R¹⁶ wherein p⁷ is 0, 1, 2 or 3;—(CH₂)_(p) ⁷—C(O)OR¹⁶; —(CH₂)_(p) ⁷—OC(O)R¹⁶; —(CH₂)_(p) ⁷—C(O)NR¹²R¹³;—(CH₂)_(p) ⁷—NR¹⁵C(O)R¹⁶; —(CH₂)_(p) ⁷—NR¹⁵C(O)NR¹²R¹³; —(CH₂)_(p)⁷—NR¹⁵C(O)OR¹⁶; —(CH₂)_(p) ⁷—SO₂R¹⁶; —(CH₂)_(p) ⁷—SO₂ NR¹²R¹³;—(CH₂)_(p) ⁷—NR¹⁵SO₂R¹⁶; —(CH₂)_(p) ⁷—OH; —(CH₂)_(p) ⁷—OR¹⁶; or phenyloptionally substituted by one or two of: a halogen atom, C₁₋₂alkyl,C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; or R⁴ and R⁵ taken togetherare —(CH₂)_(p) ²— or —C(O)—(CH₂)_(p) ²— or —(CH₂)_(p) ³—X⁵—(CH₂)_(p) ⁴—or —C(O)—X⁵—(CH₂)_(p) ⁵— as defined herein, and wherein the NR⁴R⁵heterocycle is fused to a phenyl ring optionally substituted on thephenyl by one or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl,C₁₋₂alkoxy or C₁fluoroalkoxy; and R^(5a) is C₁₋₈alkyl; C₁₋₈ fluoroalkyl;C₃₋₈cycloalkyl; phenyl optionally substituted with one or two of: ahalogen atom, C₁₋₂alkyl, trifluoromethyl, C₁₋₂alkoxy ortrifluoromethoxy; or R^(5a) has the sub-formula (x), (y) or (z) asdefined herein; R¹² and R¹³ independently are H; C₁₋₅alkyl;C₃₋₆cycloalkyl; or phenyl optionally substituted by one or two of: ahalogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy; orR¹² and R¹³ together are —(CH₂)_(n) ⁶— or —C(O)—(CH₂)_(n) ⁷— or—C(O)—(CH₂)_(n) ⁷—C(O)— or —(CH₂)_(n) ⁸—X¹²—(CH₂)_(n) ⁹— or—C(O)—X¹²—(CH₂)_(n) ¹⁰— in which: n⁶ is 3, 4, 5 or 6, n⁷ is 2, 3, 4, or5, n⁸ and n⁹ and n¹⁰ independently are 2 or 3 and X¹² is O or NR¹⁴wherein R¹⁴ is H or C₁₋₂alkyl; R¹⁵ is a hydrogen atom (H); C₁₋₄alkyl;C₃₋₆cycloalkyl; or phenyl optionally substituted by one or two of: ahalogen atom, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy or C₁fluoroalkoxy;R¹⁶ is C₁₋₄alkyl; C₃₋₆cycloalkyl; pyridinyl; or phenyl optionallysubstituted by one or two of: a halogen atom, C₁₋₂alkyl, C₁fluoroalkyl,C₁₋₂alkoxy or C₁fluoroalkoxy; and R¹⁹ is a hydrogen atom (H); C₁₋₄alkyl;—(CH₂)_(n) ²⁰—OR²⁰ wherein n²⁰ is 1, 2, 3 or 4 and R²⁰ is a hydrogenatom (H) or C₁₋₄alkyl; —CH(Me)-OH; —CH₂—SH; —CH₂—CH₂—S-Me; benzyl; or(4-hydroxyphenyl)methyl; provided that: when R³ is the heterocyclicgroup of sub-formula (bb), n¹ is 1, and Y is NR¹⁰, then: either (a) R¹⁰is not C₁₋₄alkyl, C₁₋₂fluoroalkyl or CH₂C(O)NH₂; or (b) R¹⁰ is methyland the compound is:1-ethyl-N-(2-ethylbutyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamideor1-ethyl-N-(4-fluorophenyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;and provided that: where X is OR^(5a), the compound is other than thecompound wherein R¹ is methyl, X is OEt, and R³ is cyclopentyl.
 4. Acompound or salt as claimed in claim 1 wherein R² is a hydrogen atom(H).
 5. A compound or salt as claimed in claim 1 wherein R¹ isC₁₋₃alkyl, C₁₋₂fluoroalkyl or —CH₂CH₂OH.
 6. A compound or salt asclaimed in claim 1, wherein R¹ is ethyl, n-propyl, C₂fluoroalkyl or—CH₂CH₂OH.
 7. A compound or salt as claimed in claim 1 wherein R¹ isethyl.
 8. A compound or salt as claimed in claim 1 wherein in R³ thereis one substituent or no substituent.
 9. A compound or salt as claimedin claim 1 wherein, where R³ is optionally substituted C₃₋₈cycloalkyl,then R³ is not optionally substituted C₅cycloalkyl.
 10. A compound orsalt as claimed in claim 9, wherein, where R³ is optionally substitutedC₃₋₈cycloalkyl, then R³ is optionally substituted C₆₋₈cycloalkyl.
 11. Acompound or salt as claimed in claim 9, wherein, where R³ is optionallysubstituted C₃₋₈cycloalkyl, then R³ is optionally substitutedcyclohexyl.
 12. A compound or salt as claimed in claim 1 wherein, whereR³ is optionally substituted C₃₋₈cycloalkyl, then the one or twooptional substituents is or independently are: oxo (═O); OH; NHR²¹wherein R²¹ is a hydrogen atom (H); methyl; —CH₂F; —CHF₂; —C(O)OR²³wherein R²³ is H; fluoro; hydroxyimino (═N—OH); or (C₁₋₂alkoxy)imino(═N—OR²⁶ where R²⁶ is C₁₋₂alkyl).
 13. A compound or salt as claimed inclaim 1 wherein, where R³ is optionally substituted C₃₋₈cycloalkyl, thenthe one or two optional substituents is or independently are OH, oxo(═O) or hydroxyimino (═N—OH).
 14. A compound or salt as claimed in claim1 wherein, where R³ is optionally substituted C₃₋₈cycloalkyl, then theone or two optional substituents if present is or are substituent(s) atthe 3-, 4- or 5-position(s) of the R³ cycloalkyl ring, wherein the1-position of the R³ cycloalkyl ring is the connection point to the —NH—in formula (I) or (IA) or (IB).
 15. A compound or salt as claimed inclaim 1 wherein, where R³ is optionally substituted C₆cycloalkyl, thenR³ is cyclohexyl, 3-hydroxy-cyclohexyl, 4-oxo-cyclohexyl,4-(hydroxyimino)cyclohexyl, 4-(C₁₋₂alkoxyimino)cyclohexyl,1-methylcyclohexyl or 3-methylcyclohexyl.
 16. A compound or salt asclaimed in claim 1 wherein, where R³ is optionally substitutedmono-unsaturated-C₅₋₇cycloalkenyl, then R³ is optionally substitutedmono-unsaturated-C₆cycloalkenyl, and wherein the R³ cycloalkenyl isoptionally substituted with one or two substituents being fluoro ormethyl.
 17. A compound or salt as claimed in claim 1 wherein, where R³is the heterocyclic group of sub-formula (aa), (bb) or (cc), then Y isO, S, SO₂, NH or N—C(O)methyl.
 18. A compound or salt as claimed inclaim 1 wherein, where R³ is the heterocyclic group of sub-formula (aa),(bb) or (cc), then Y is
 0. 19. A compound or salt as claimed in claim 1wherein R¹⁰ is a hydrogen atom (H) or C(O)methyl.
 20. A compound or saltas claimed in claim 1 wherein where R³ is the heterocyclic group ofsub-formula (aa), (bb) or (cc), then R³ is the heterocyclic group ofsub-formula (bb) and n¹ is
 1. 21. A compound or salt as claimed in claim1 wherein, in R³, the heterocyclic group of sub-formula (aa), (bb) or(cc) is unsubstituted (wherein, where Y is NR¹⁰, R¹⁰ is not classifiedas a substituent).
 22. A compound or salt as claimed in claim 1 wherein,in the R³ heterocyclic group of sub-formula (aa), (bb) or (cc), the oneor two optional substituents is or are oxo (═O).
 23. A compound or saltas claimed in claim 1 wherein when R³ is the heterocyclic group ofsub-formula (aa) then Y is O, S, SO₂ or NH, and when R³ is theheterocyclic group of sub-formula (bb) and Y is NR¹⁰, then R¹⁰ is notC₁₋₄alkyl, C₁₋₂fluoroalkyl or CH₂C(O)NH₂.
 24. A compound or salt asclaimed in claim 1 wherein, where R³ is a bicyclic group of sub-formula(dd) or (ee), then R³ is of sub-formula (ee) wherein Y¹, Y² and Y³ areall CH₂.
 25. A compound or salt as claimed in claim 1 wherein NHR³ is ofsub-formula (a), (a1), (b), (c), (c1), (c2), (c3), (c4), (c5), (c6),(c7), (d), (e), (f), (g), (g1), (g2), (g3), (g4), (h), (i), (j), (k),(k1), (L), (m), (m1), (m2), (m3), (m4), (m5), (n), (o), (o1), (o2),(o3), (o4), (o5), (p), (p1), (p2), (p3), (p4), (p5), (p6), (p7), (p8) or(q):


26. A compound or salt as claimed in claim 25, wherein NHR³ is ofsub-formula (c), (c1), (c2), (c3), (c4), (c5), (c6), (c7), (d), (e),(f), (g1), (g4), (h), (i), (j), (k), (k1), (L), (m), (m1), (m2), (m3),(m5), (n), (o), (o1), (o2), (o3), (o4), (o5), (p), (p2), (p3), (p5),(p6), (p7) or (q).
 27. A compound or salt as claimed in claim 25,wherein NHR³ is of sub-formula (c), (d), (e), (f), (g1), (h), (i), (j),(k), (m), (m1), (n), (o), (o1), (p), or (q).
 28. A compound or salt asclaimed in claim 26, wherein NHR³ is of sub-formula (c), (c1), (c4),(c5), (h), (i), (j), (k), (m1), (m2), (n), (o), (o2), (o3), (p2), (p5),(p6) or (q).
 29. A compound or salt as claimed in claim 26, wherein NHR³is of sub-formula (c), (h), (k), (n), (o) or (o2).
 30. A compound orsalt as claimed in claim 25, wherein NHR³ is sub-formula (h).
 31. Acompound or salt as claimed in claim 1 wherein X is NR⁴R⁵.
 32. Acompound or salt as claimed in claim 1 wherein R⁴ is a hydrogen atom(H), C₁₋₄alkyl, —(CH₂)_(n) ³—OH or —(CH₂)_(n) ³—NR¹²R¹³ wherein n³ is 2and R¹² and R¹³ independently are H or C₁alkyl.
 33. A compound or saltas claimed in claim 1 wherein R⁴ is a hydrogen atom (H).
 34. A compoundor salt as claimed in claim 1 wherein R⁵ is: C₁₋₈alkyl; C₁₋₃fluoroalkyl;C₃₋₈cycloalkyl (unsubstituted); unsubstituted —(CH₂)_(n)⁴—C₅₋₆cycloalkyl wherein n⁴ is 1 or 2; —(CH₂)_(n) ⁵—R¹¹ wherein n⁵ is 2or 3, and each substituent R¹¹, independently of any other R¹¹substituent present, is C₁₋₄alkoxy, —NR¹⁵—C(O)—NH—R¹⁵, or —NR¹⁵—SO₂R¹⁶,and any R¹¹ substituent which is alkoxy is not substituted at any carbonatom, of the R⁵ substituted alkyl, which is bonded to the nitrogen ofNR⁴R⁵; or R⁵ is —(CH₂)_(n) ¹¹—C(O)R¹⁶; —(CH₂)_(n) ¹²—C(O)NR¹²R¹³;—(CH₂)_(n) ¹²—C(O)OR¹⁶; —(CH₂)_(n) ¹²—SO₂—NR¹²R¹³; —(CH₂)_(n) ¹²—SO₂R¹⁶;or —(CH₂)_(n) ¹²—CN wherein n¹¹ is 1 or 2 and n¹² is 1 or
 2. 35. Acompound or salt as claimed in claim 1 wherein R⁵ is —(CH₂)_(n) ¹³—Het,n¹³ is 0, 1 or 2, and Het is a 5- or 6-membered saturated saturatedheterocyclic ring.
 36. A compound or salt as claimed in claim 1 whereinR⁵ is phenyl optionally substituted with, independently, one or two of:a halogen atom; C₁₋₂alkyl; C₁₋₂fluoroalkyl; C₁₋₂alkoxy;trifluoromethoxy; C₁₋₂alkylsulphonyl (C₁₋₂alkyl-SO₂—);C₁₋₂alkyl-SO₂—NH—; R⁷R⁸N—SO₂—; R⁷R⁸N—CO—; —NR¹⁵—C(O)R¹⁶; R⁷R⁸N; OH;C₁₋₂alkoxymethyl; C₁₋₂alkyl-SO₂—CH₂—; cyano (CN); or phenyl optionallysubstituted by one of fluoro, C₁₋₂alkyl, C₁fluoroalkyl, C₁₋₂alkoxy orC₁fluoroalkoxy.
 37. A compound or salt as claimed in claim 35, whereinR⁵ is phenyl optionally substituted with one or two of: a halogen atom,C₁₋₂alkyl, trifluoromethyl, C₁₋₂alkoxy, trifluoromethoxy, R⁷R⁸N—SO₂—,R⁷R⁸N—CO—, or C₁₋₂alkyl-SO₂—CH₂—.
 38. A compound or salt as claimed inclaim 1 wherein R⁵ has the sub-formula (x) or (y) or (y1) or (z).
 39. Acompound or salt as claimed in claim 1 wherein R⁵ has the sub-formula(x).
 40. A compound or salt as claimed in claim 1 wherein n=1, m=1, andr=1.
 41. A compound or salt as claimed in claim 1 wherein, insub-formula (x), (y) and/or (y1): none, one or two of A, B, D, E and Fare nitrogen; none, one, two or three of A, B, D, E and F are CR⁶; andthe remaining of A, B, D, E and F are CH.
 42. A compound or salt asclaimed in claim 41, wherein, in sub-formula (x), (y) and/or (y1), noneor one of A, B, D, E and F are nitrogen.
 43. A compound or salt asclaimed in claim 1 wherein in sub-formula (x), (y), (y1) and/or (z),each R⁶, independently of any other R⁶ present, is a fluorine, chlorine,bromine or iodine atom, methyl, ethyl, n-propyl, isopropyl, C₄alkyl,trifluoromethyl, —CH₂OH, methoxy, ethoxy, C₁fluoroalkoxy, OH,C₁₋₃alkylS(O)₂—, C₁₋₃alkylS(O)₂—NH—, Me₂N—S(O)₂—, H₂N—S(O)₂—, —CONH₂,—CONHMe, —CO₂H, cyano (CN), NMe₂, t-butoxymethyl, or C₁₋₃alkylS(O)₂—CH₂.44. A compound or salt as claimed in claim 43, wherein in sub-formula(x), (y), (y1) and/or (z), each R⁶, independently of any other R⁶present, is a fluorine, chlorine or bromine atom, methyl, ethyl,n-propyl, isopropyl, trifluoromethyl, —CH₂OH, methoxy, difluoromethoxy,methylsulphonyl, methyl-SO₂—NH— or methyl-SO₂—CH₂—.
 45. A compound orsalt as claimed in claim 1 wherein R⁵ is of sub-formula (x) and is:benzyl, (monoalkyl-phenyl)methyl, [mono(fluoroalkyl)-phenyl]methyl,(monohalo-phenyl)methyl, (monoalkoxy-phenyl)methyl,[mono(fluoroalkoxy)-phenyl]methyl,[mono(N,N-dimethylamino)-phenyl]methyl,[mono(methyl-SO₂—NH—)-phenyl]methyl, [mono(methyl-SO₂—)-phenyl]methyl,(dialkyl-phenyl)methyl, (monoalkyl-monohalo-phenyl)methyl,[mono(fluoroalkyl)-monohalo-phenyl]methyl, (dihalo-phenyl)methyl,(dihalo-monoalkyl-phenyl)methyl,[dihalo-mono(hydroxymethyl)-phenyl]methyl, or (dialkoxy-phenyl)methyl.46. A compound or salt as claimed in claim 45, wherein R⁵ is:(monoC₁₋₃alkyl-phenyl)methyl; (monoC₁fluoroalkyl-phenyl)methyl;(monoC₁₋₂alkoxy-phenyl)methyl; [mono(C₁fluoroalkoxy)-phenyl]methyl;(diC₁₋₂alkyl-phenyl)methyl; (monoC₁₋₂alkyl-monohalo-phenyl)methyl;(dihalo-phenyl)methyl; (dihalo-monoC₁₋₂alkyl-phenyl)methyl; or[dihalo-mono(hydroxymethyl)-phenyl]methyl.
 47. A compound or salt asclaimed in claim 46, wherein R⁵ is: (4-C₁₋₃alkyl-phenyl)methyl;(4-C₁fluoroalkyl-phenyl)methyl; (4-C₁₋₂alkoxy-phenyl)methyl;(4-C₁fluoroalkoxy-phenyl)methyl; (3,4-dimethyl-phenyl)methyl;(2,4-dimethyl-phenyl)methyl; (3,5-dimethyl-phenyl)methyl;(2,3-dimethyl-phenyl)methyl; (2,5-dimethyl-phenyl)methyl;(4-methyl-3-chloro-phenyl)methyl; (3-methyl-4-chloro-phenyl)methyl;(2-methyl-4-chloro-phenyl)methyl; (2-chloro-4-fluorophenyl)methyl;(2,4-difluoro-phenyl)methyl, (4-bromo-2-fluorophenyl)methyl;(4-chloro-2-fluorophenyl)methyl; (3,4-dichloro-phenyl)methyl;(2,4-dichloro-phenyl)methyl; (2,6-dichloro-phenyl)methyl;(2,3-dichloro-phenyl)methyl; (2,4-dichloro-6-methyl-phenyl)methyl; or[2,3-dichloro-6-(hydroxymethyl)-phenyl]methyl.
 48. A compound or salt asclaimed in claim 1 wherein R⁵ has the sub-formula (z), r is 1, none orone of J, L, M or Q is CR⁶, and if one of J, L, M or Q is CR⁶ then R⁶ ismethyl or C₁fluoroalkyl, and R⁹ is a hydrogen atom (H) or methyl.
 49. Acompound or salt as claimed in claim 1, which is: ethyl4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl4-[(1-acetylpiperidin-4-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl1-ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl1-ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl1-ethyl-4-(tetrahydrothien-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl4-(cyclopropylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,N-benzyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-cyclopentyl-4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-cyclopentyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-cyclopentyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetylpiperidin-4-yl)amino]-N-cyclopentyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-cyclopentyl-1-ethyl-5-(pyrrolidin-1-ylcarbonyl)-1H-pyrazolo[3,4-b]pyridin-4-amine,N-cyclohexyl-1-ethyl-5-(pyrrolidin-1-ylcarbonyl)-1H-pyrazolo[3,4-b]pyridin-4-amine,1-ethyl-5-(pyrrolidin-1-ylcarbonyl)-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine,4-(cyclopentylamino)-1-ethyl-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(pyridin-4-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-4-(cyclopentylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(acetylpiperidin-4-yl)amino]-N-benzyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclopentylamino)-1-ethyl-N-(2-ethylbutyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(2-ethylbutyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(2-ethylbutyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(2-ethylbutyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetylpiperidin-4-yl)amino]-1-ethyl-N-(2-ethylbutyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclopentylamino)-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-fluorophenyl)-4-[(1-methylpiperidin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetylpiperidin-4-yl)amino]-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclopentylamino)-1-ethyl-N-n-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-n-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetylpiperidin-4-yl)amino]-1-ethyl-N-n-propyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetylpiperidin-4-yl)amino]-1-ethyl-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-4-(cyclopentylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-4-(cyclohexylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclopentylamino)-N-(2-ethylbutyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-(2-ethylbutyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2 ethylbutyl)-1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclopentylamino)-N-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(4-fluorophenyl)-1-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclopentylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetylpiperidin-4-yl)amino]-N-benzyl-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N,N-dimethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-isopropyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-1-ethyl-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl1-ethyl-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-1-ethyl-4-(tetrahydrothien-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-4-(cyclopropylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-1-ethyl-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-fluorophenyl)-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-fluorophenyl)-4-[(3R)-tetrahydrofuran-3-ylamino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-fluorophenyl)-4-(tetrahydrothien-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclopropylamino)-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-1-ethyl-N-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[4-(methylsulfonyl)benzyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[3-(methylsulfonyl)benzyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-{[5-methoxy-6-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine,N-[(5-chloropyridin-2-yl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(4-chlorobenzyl)-1-ethyl-N-isopropyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3-chlorobenzyl)-1-ethyl-N-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2-tert-butoxyethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(1,3-thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(pyrimidin-4-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(2-methyl-1,3-thiazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[3-(tert-butoxymethyl)benzyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{2-[methyl(methylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(pyrazin-2-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-5-{[4-(pyridin-2-ylcarbonyl)piperazin-1-yl]carbonyl}-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine,N-(2-chloro-6-fluorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[3-(aminocarbonyl)benzyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{4-[(methylamino)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(1-methyl-1H-imidazol-4-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{2-[(anilinocarbonyl)amino]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(1H-tetraazol-5-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,tert-butyl4-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)piperidine-1-carboxylate,1-ethyl-N-{3-[(methylsulfonyl)amino]propyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[2-(dimethylamino)benzyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(1-ethylpyrrolidin-2-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(tetrahydrofuran-2-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-tetrahydro-2H-pyran-4-yl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{4-[(dimethylamino)sulfonyl]benzyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{3-[(methylsulfonyl)amino]benzyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-methoxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[3-(2-oxopyrrolidin-1-yl)propyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(pyridin-3-ylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(1-methylpiperidin-4-yl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(1-ethylpropyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(2-piperidin-1-ylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(3-morpholin-4-ylpropyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3-ethoxypropyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(cyclohexylmethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[3-(dimethylamino)propyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-neopentyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-methoxybenzyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{2-[(phenylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[2-(acetylamino)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{2-[(methylsulfonyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{2-[(2-methoxyphenyl)(methyl)amino]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(2-oxo-2-phenylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2,5-difluorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N,1-diethyl-N-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-cyclopropyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2-amino-2-oxoethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(3-methoxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3,4-difluorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,ethyl-3-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)propanoate,N-(1-benzylpiperidin-4-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-butyl-4-{[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}piperazine-1-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(1,3,4-thiadiazol-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(2-oxoimidazolidin-1-yl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3,4-dimethoxybenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3-chlorobenzyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-5-[(4-methylpiperazin-1-yl)carbonyl]-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine,1-ethyl-N-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-5-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-N-tetrahydro-2H-pyran-4-yl-1H-pyrazolo[3,4-b]pyridin-4-amine,1-ethyl-N-{4-[(methylsulfonyl)methyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[3-(dimethylamino)-3-oxopropyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(1-methyl-1H-imidazol-5-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{4-[(methylamino)sulfonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2-cyanoethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-methyl-N-[(1-methyl-1H-imidazol-2-yl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(2-thien-2-ylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[2-(4-chlorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(2-methoxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,ethyl-4-(cyclohexylamino)-1-(3-ethoxy-3-oxopropyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl1-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,N-[4-(methylsulfonyl)benzyl]-1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(4-fluorophenyl)-1-n-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,ethyl1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl4-(cyclohexylamino)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,4-(cyclohexylamino)-1-ethyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl4-(cyclohexylamino)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(4-fluorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-6-methyl-N-[4-(trifluoromethyl)benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-1-ethyl-4-[(2-oxoazepan-3-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-1-ethyl-4-[(3-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-1-ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-1-ethyl-4-[(3-hydroxycyclopentyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-benzyl-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(2-hydroxy-1-methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,methyl(2S)-2-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)-3-hydroxypropanoate,ethyl1-ethyl-4-[(4-hydroxycyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl4-[(4-aminocyclohexyl)amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl-N-[(1-oxido-3-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(1-oxido-2-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(1-oxido-4-pyridinyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(cis-4-aminocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(4-methylcyclohexyl)amino]-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(3-methylcyclohexyl)amino]-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(1-methylcyclohexyl)amino]-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1R,2S,4S)-bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-{[(3S)-2-oxo-3-pyrrolidinyl]amino}-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(2,5-dioxo-3-pyrrolidinyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(1-azabicyclo[2.2.2]oct-3-ylamino)-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(1-methylcyclohexyl)amino]-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclobutylamino)-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cycloheptylamino)-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(4-methylcyclohexyl)amino]-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(3-methylcyclohexyl)amino]-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1R,2S,4S)-bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(cis-4-aminocyclohexyl)amino]-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cycloheptylamino)-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclobutylamino)-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1R,2S,4S)-bicyclo[2.2.1]hept-2-ylamino]-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(4-methylcyclohexyl)amino]-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(3-methylcyclohexyl)amino]-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(1-methylcyclohexyl)amino]-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(cis-4-aminocyclohexyl)amino]-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cycloheptylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclobutylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-[(3-methylcyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-[(4-methylcyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1R,2S,4S)-bicyclo[2.2.1]hept-2-ylamino]-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-[(1-methylcyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(cis-4-aminocyclohexyl)amino]-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{4-[(methylsulfonyl)methyl]phenyl}-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,4-dimethylphenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3,4-dichlorophenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[4-(dimethylamino)phenyl]methyl}-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-({4-[(difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(4-oxocyclohexyl)amino]-N-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-fluorophenyl)-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(4-oxocyclohexyl)amino]-N-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(1-acetyl-4-piperidinyl)-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N,1-diethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide1-ethyl-4-[(4-oxocyclohexyl)amino]-N-(1,3-thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-({4-[(difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-N-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{4-[(methylsulfonyl)methyl]phenyl}-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-fluorophenyl)-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(2-pyridinylmethyl)-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(1-acetyl-4-piperidinyl)-1-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N,1-diethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-N-(1,3-thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(4,4-difluorocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-[(4-fluoro-3-cyclohexen-1-yl)amino]-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-[(3,4-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-[(3-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-[(3,4-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-[(2,5-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-{[3-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-[(2,6-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-[(3-chlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-({4-[(dimethylamino)sulfonyl]phenyl}methyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-{[2-(dimethylamino)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-[(2,4-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-[(2-chloro-6-fluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-({4-[(difluoromethyl)oxy]phenyl}methyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-{[3-chloro-4-(methyloxy)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-[(5-chloro-2-pyridinyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-(1,3-thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-(2,2-diphenylethyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-{[4-(aminosulfonyl)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-({3-[(methylamino)carbonyl]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-N-{[4-(aminocarbonyl)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(1-acetyl-4-piperidinyl)amino]-1-ethyl-N-{[6-(methyloxy)-3-pyridinyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-4-piperidinyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-piperidinylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[1-(ethylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[1-(cyclopentylsulfonyl)-4-piperidinyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[1-(methylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{1-[(phenylmethyl)sulfonyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[1-(phenylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[1-(propylsulfonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[1-(cyclopropylcarbonyl)-4-piperidinyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[1-(3-furanylcarbonyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[1-(3,3-dimethylbutanoyl)-4-piperidinyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[1-(2-ethylbutanoyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[1-(cyclopentylacetyl)-4-piperidinyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[1-(2-methylpropanoyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[1-(tetrahydro-2H-pyran-4-ylcarbonyl)-4-piperidinyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(1-propanoyl-4-piperidinyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[1-(N-acetylglycyl)-4-piperidinyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[1-(4-morpholinylacetyl)-4-piperidinyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{1-[(4-oxocyclohexyl)carbonyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[1-(1-piperidinylacetyl)-4-piperidinyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{1-[(1-methyl-5-oxo-3-pyrrolidinyl)carbonyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{1-[(3-methyl-3-oxetanyl)carbonyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{1-[(4-fluorophenyl)acetyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[1-(3,3-dimethylbutanoyl)-4-piperidinyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[1-cyclopentylacetyl)-4-piperidinyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[1-(cyclopropylcarbonyl)-4-piperidinyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-({1-[(4-oxocyclohexyl)carbonyl]-4-piperidinyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-({1-[(4-fluorophenyl)acetyl]-4-piperidinyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-({1-[(1-methyl-5-oxo-3-pyrrolidinyl)carbonyl]-4-piperidinyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,methyl3-[(1-ethyl-5-{[(phenylmethyl)amino]carbonyl}-1H-pyrazolo[3,4-b]pyridin-4-yl)amino]cyclohexanecarboxylate,3-[(1-ethyl-5-{[(phenylmethyl)amino]carbonyl}-1H-pyrazolo[3,4-b]pyridin-4-yl)amino]cyclohexanecarboxylicacid,1-ethyl-N-(phenylmethyl)-4-(4-piperidinylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,ethyl1-ethyl-4-({1-[(methyloxy)acetyl]-4-piperidinyl}amino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,ethyl1-(1-methylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,4-(cyclohexylamino)-1-ethyl-N-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-fluorophenyl)-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-6-methyl-N-{[4-(methylsulfonyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[3-(1-piperidinylcarbonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[4-(1-methylethyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(2-fluorophenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{3-[(dimethylamino)carbonyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{4-[(difluoromethyl)oxy]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{4-[acetyl(methyl)amino]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[4-(4-morpholinyl)-2-(trifluoromethyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-4-pyridinyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{4-[(4-methyl-1-piperazinyl)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(2-oxo-1-pyrrolidinyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[3-(methylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{3-[acetyl(methyl)amino]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{3-[(methylsulfonyl)amino]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(4-fluoro-2-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(4-chlorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3-chloro-2-cyanophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[3-(1-piperidinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(methylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{2-[acetyl(methyl)amino]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[3-(4-morpholinylcarbonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(4-chloro-3-cyanophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(3-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3-chlorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[3-[(acetylamino)methyl]-4-(methyloxy)phenyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[4-(1-piperidinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3-{[cyclohexyl(methyl)amino]carbonyl}phenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(4-morpholinyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{3-[(acetylamino)sulfonyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3-chloro-4-hydroxyphenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{4-[(methylsulfonyl)amino]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{3-[(methylamino)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-3-pyridinyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3,4-dichlorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[3-(aminosulfonyl)-4-chlorophenyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[3-(4-morpholinyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[4-(4-morpholinylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{2-[(4-methyl-1-piperazinyl)carbonyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{2-[(difluoromethyl)carbonyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[2-Chloro-4-(Iphenyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{2-[(acetylamino)methyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2-chlorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3-chloro-2-fluorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(3-fluorophenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2-Cyano-3-fluorophenyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[4-(propylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{4-[(dimethylamino)carbonyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[4-(methylsulfonyl)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{4-[(acetylamino)methyl]phenyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[2-(aminosulfonyl)ethyl]-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2-amino-2-oxoethyl)-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{2-[(methylsulfonyl)amino]ethyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{[3-(methylsulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[3-(aminocarbonyl)phenyl]methyl}-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(tetrahydro-2-furanylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-({4-[(dimethylamino)sulfonyl]phenyl}methyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(5-chloro-2-pyridinyl)methyl]-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{[4-(methylsulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{[6-(methyloxy)-3-pyridinyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{4-[(methylamino)carbonyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-({3-[(methylamino)carbonyl]phenyl)methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[4-(aminocarbonyl)phenyl]methyl}-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-[(4-hydroxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-[(3,4-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{[4-(trifluoromethyl)phenyl]methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-({3-[(methylsulfonyl)amino]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-[(2,5-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-[(4-methylphenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(2-{4-[(methylsulfonyl)amino]phenyl}ethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylaminoo)-1-ethyl-N-[(2-hydroxyphenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-[(3,4-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-[(3,5-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{[2-(methylsulfinyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-[2-(4-hydroxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(2-[4-(aminosulfonyl)phenyl]ethyl}-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-({2-[(methylamino)carbonyl]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{[2-(methylsulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,methyl2-[({[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate,4-(cyclohexylamino)-1-ethyl-N-{2-[4-(methylsulfonyl)phenyl]ethyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[4,5-bis(methyloxy)-2,3-dihydro-1H-inden-2-yl]-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-[2-(4-fluorophenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-[2-(4-methylphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{2-[4-(methyloxy)phenyl]ethyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,4-(cyclohexylamino)-N-[(3,5-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-(2,3-dihydro-1H-inden-1-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-{[4-(dimethylamino)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,4-(cyclohexylamino)-1-ethyl-N-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[2,4-bis(methyloxy)phenyl]methyl}-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(6-chloro-2-pyridinyl)methyl]-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,N-({2-[acetyl(methyl)amino]phenyl}methyl)-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,4-(cyclohexylamino)-1-ethyl-N-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-[(2,6-dichlorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,methyl3-[({[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate,4-(cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,methyl4-[({[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate,4-(cyclohexylamino)-1-ethyl-N-(1H-tetrazol-5-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-({4-[(difluoromethyl)oxy]phenyl}methyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-[(2-methyl-1,3-thiazol-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2-chloro-6-fluorophenyl)methyl]-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[2-(aminocarbonyl)phenyl]methyl}-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-{[2-(dimethylamino)phenyl]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-[(4-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{[3-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-N-[(2,6-difluorophenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-[(3-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-[(6-oxo-1,6-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-(cyclohexylamino)-1-ethyl-N-(3-pyridinylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[({[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoicacid,3-[({[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoicacid,4-(cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamidehydrochloride,4-(cyclohexylamino)-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamidemethanesulphonate,N-({2-[(1,1-dimethylethyl)oxy]-3-pyridinyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,N-[(3-chloro-4-methylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(4-chloro-2-methylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-({2-[(difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-({2-[(1-methylethyl)oxy]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-({3-[(1-methylethyl)oxy]phenyl)methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(3-[(difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[4-hydroxy-3-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(5-acetyl-2-hydroxyphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-{2-[3-(trifluoromethyl)phenyl]ethyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[4-(acetylamino)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(3-hydroxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[2-(3-chlorophenylethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-(2-{4-[(trifluormethyl)oxy]phenyl}ethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{2-[3-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[2-(4-acetylphenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[2-(3,4-dichlorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{2-[3-(aminosulfonyl)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{2-[3,4-Bis(methyloxy)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-2-(2,3-dichlorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-3H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{2-[3,5-bis(methyloxy)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{2-[3-methyl-4-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[2-(2,6-dichlorophenyl)ethyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{2-[2,6-bis(methyloxy)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(2-methylphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[4,5-bis(methyloxy)-2,3-dihydro-1H-inden-2-yl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{2-[4-(aminosulfonyl)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[2-(methylsulfinyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(2-phenylethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[4-(dimethylamino)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(4-fluorophenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(4-methylphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[3-(aminosulfonyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(4-methylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,methyl2-[({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate,N-[(6-chloro-2-pyridinyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,N-(2,3-dihydro-1H-inden-1-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-({2-[acetyl(methyl)amino]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(1S)-2,3-dihydro-1H-inden-1-yl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(1R)-2,3-dihydro-1H-inden-1-yl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-({3-[(methylsulfonyl)amino]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(phenylmethyl)-N-propyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[2-(dimethylamino)ethyl]-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-butyl-1-ethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N,1-diethyl-N-(phenylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(1-phenyl-4-piperidinyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{1-[(ethylamino)carbonyl]-4-piperidinyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,formicacid-1-ethyl-N-[1-methyl-2-(4-methyl-1-piperazinyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide(1:1),methyl-[4-({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)-1-piperidinyl]acetate,1-ethyl-N-{[4-(4-morpholinylmethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,1-ethyl-N-({3-[(4-methyl-1-piperazinyl)methyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,N-{[5-(aminocarbonyl)-3-pyridinyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,1-ethyl-N-{[4-(1-methylethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[3-(cyclopentyloxy)-4-(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-({4-[(4-methyl-1-piperazinyl)methyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,N-[(2,4-dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,4-dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{2-[2-chloro-3-(methyloxy)phenyl]ethyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,methyl3-[({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate,1-ethyl-N-{[3-(1-pyrrolidinylmethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidetrifluoroacetate,1-ethyl-N-(2-{4-[(methylsulfonyl)amino]phenyl}ethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[2,5-bis(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[2,6-bis(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(2-fluorophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3,5-difluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(4-chlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-cyclohexyl-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{2-[4-(methylsulfonyl)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-({4-[(cyclopropylamino)carbonyl]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[4-(4-methyl-1-piperazinyl)phenyl]methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[4-(1-pyrrolidinylmethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[6-(methyloxy)-1-oxo-2,3-dihydro-1H-inden-2-yl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,5-dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3,5-dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,3-difluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[2-(methylsulfonyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(3-hydroxyphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[3,5-bis(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[2-(4-hydroxyphenyl)ethyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3,5-dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[2,4-bis(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[2-(methyloxy)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,4-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-({2-[(methylamino)carbonyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{2-[4-(methyloxy)phenyl]ethyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2-chlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(2-hydroxyphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(1,3-benzodioxol-5-ylmethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[3-(methyloxy)phenyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(cyclohexylmethyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,methyl4-[({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoate,N-[(3,4-dichlorophenyl)methyl]-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[4-(aminocarbonyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,6-difluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,{[3-(aminocarbonyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(4-hydroxyphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[6-(methyloxy)-3-pyridinyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-(2-pyridinylmethyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-{[3-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[4-(2-amino-2-oxoethyl)phenyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-({4-[(methylamino)carbonyl]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl1-N-{4-[2-(methylamino)-2-oxoethyl]phenyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl1-N-[(3-fluorophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-({4-[(methylsulfonyl)amino]phenyl}methyl)-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[4-(aminosulfonyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[2-(aminocarbonyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-({4-[(difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(f 3-[(dimethylaminomethyl]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[3-chloro-4-(methyloxy)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(1-acetyl-4-piperidinyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-{[2-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-(5-chloro-2,3-dihydro-1H-inden-2-yl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-({3-[(acetylamino)methyl]phenyl}methyl)-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(4-fluorophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(2-ethylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[2-fluoro-5-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[(2,3,4-trifluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(4-chloro-2-fluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(4-bromo-2-fluorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3,5-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,3-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,3-dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(4-cyanophenyl)methyl]-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(4-bromophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[5-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethylN-[(4-iodophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[4-(1,1-dimethylethyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3-cyanophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,6-dichlorophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(5-chloro-2-methylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3,5-dibromophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethylN-[(4-ethylphenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[3-fluoro-4-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(2-iodophenyl)methyl]-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2-bromophenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[4-(hydroxymethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-ethyl-N-{[3-(hydroxymethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[3-(hydroxymethyl)-2-methylphenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[2,3-dichloro-6-(hydroxymethyl)phenyl]methyl}-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,4-dichloro-6-methylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[4-(2-methylpropyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,5-dimethylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-N-[(2,4,5-trifluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[2-fluoro-4-(trifluoromethyl)phenyl]methyl}-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2-chloro-6-methylphenyl)methyl]-1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoicacid sodium salt,3-[({[1-ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]carbonyl}amino)methyl]benzoicacid, ethyl1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[4-(dimethylamine)phenyl]methyl}-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-({4-[(ethyloxy)imino]cyclohexyl}amino)-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-({4-[(methyloxy)imino]cyclohexyl}amino)-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(4-{[(1,1-dimethylethyl)oxy]imino}cyclohexyl)amino]-1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-{[4-(methyloxy)phenyl]methyl}-4-[(7-oxohexahydro-1H-azepin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,ethyl1-ethyl-4-[(7-oxohexahydro-1H-azepin-4-yl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,4-{[cis-4-(butylamino)cyclohexyl]amino}-N-(2,3-dihydro-1H-inden-2-yl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(trans-4-aminocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(trans-2-aminocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(cis-2-aminocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,4-[(3-aminocyclohexyl)amino]-1-ethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,ethyl1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxylate,N,1-diethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-thylN-(4-fluorophenyl)-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-N-(1,3-thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-N-[(4-fluorophenyl)methyl]-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-N-{[4-(methylsulfonyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-{[3,4-bis(methyloxy)phenyl]methyl}-1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-N-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-N-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,4-dimethylphenyl)methyl]-1-ethyl-4-{[(1SR,3RS)-3-hydroxycyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,3-dichlorophenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3-chloro-4-methylphenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(4-chloro-2-methylphenyl)methyl]-1-ethyl-4-[(4-oxocyclohexyl)amino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,4-dimethylphenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3,4-dimethylphenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(2,3-dichlorophenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(3-chloro-4-methylphenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-[(4-chloro-2-methylphenyl)methyl]-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,N-({4-[(difluoromethyl)oxy]phenyl}methyl)-1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide,or1-ethyl-4-{[4-(hydroxyimino)cyclohexyl]amino}-N-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;or a salt thereof.
 50. A compound or salt as claimed in claim 1, whichis a compound of Example 260, 261, 263, 266, 431, 493, 494, 518, 528,584, 626, 643, 653, 679, 680, 681, 682, 683, 684, 685 or 686, as definedby the structures and/or names described herein, or a salt thereof. 51.A compound or salt as claimed in claim 1, which is a compound of Example21, 22, 83, 100, 109, 167, 172, 178 or 600, as defined by the structuresand/or names described herein, or a salt thereof. 52-55. (canceled) 56.A pharmaceutical composition comprising a compound of formula (I) asdefined in claim 1 or a pharmaceutically acceptable salt thereof, andone or more pharmaceutically acceptable carriers and/or excipients. 57.A pharmaceutical composition as claimed in claim 56 which is suitablefor and/or adapted for inhaled administration.
 58. A pharmaceuticalcomposition as claimed in claim 57, in which the compound or salt is ina particle-size-reduced form.
 59. A pharmaceutical composition asclaimed in claim 58, wherein the particle size (D50 value) of thesize-reduced compound or salt is about 0.5 to about 10 microns.
 60. Acomposition as claimed in claim 56, for the treatment and/or prophylaxisof an inflammatory and/or allergic disease or cognitive impairment in amammal such as a human.
 61. (canceled)
 62. A method of treatment and/orprophylaxis of an inflammatory and/or allergic disease or cognitiveimpairment in a mammal such as a human in need thereof, which methodcomprises administering to the mammal suffering from same, atherapeutically effective amount of a compound of formula (I), asdefined in claim 1 or a pharmaceutically acceptable salt thereof.
 63. Acomposition, the use or a method as claimed in claim 62, wherein thecomposition or medicament or method is for the treatment and/orprophylaxis of chronic obstructive pulmonary disease (COPD), asthma,rheumatoid arthritis or allergic rhinitis in a mammal such as a human.64-67. (canceled)
 68. A composition comprising a compound of formula(I), as defined in claim 1 or a pharmaceutically acceptable saltthereof, together with a β₂-adrenoreceptor agonist, an anti-histamine,an anti-allergic, or an anti-inflammatory agent; alone or combined withat least one pharmaceutically acceptable carriers.
 69. A composition asclaimed in claim 68, comprising the compound of formula (I) or thepharmaceutically acceptable salt thereof, together with aβ₂-adrenoreceptor agonist and at least one pharmaceutically acceptablecarrier.
 70. A composition comprising a compound of formula (I), asdefined in claim 1 or a pharmaceutically acceptable salt thereof,together with a muscarinic (M) receptor antagonist and at least onepharmaceutically acceptable carrier.
 71. A composition as claimed inclaim 70, wherein the muscarinic (M) receptor antagonist is a M₃receptor antagonist and at least one pharmaceutically acceptablecarrier. 72-74. (canceled)